Intermediates of 2-Substituted Carbapenem Derivatives and Process for Production Thereof

ABSTRACT

The present invention relates to compounds represented by formula (1) and a process for producing the same. The use of these compounds can realize the production of carbapenem derivatives having potent antimicrobial activity and a wide antimicrobial spectrum in a safe and cost-effective manner.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel synthetic intermediates for theproduction of carbapenem derivatives, which have excellent antimicrobialactivity and a broad antimicrobial spectrum, and a process for theproduction thereof.

2. Related Art

Carbapenem derivatives have high antimicrobial activity and a broadexcellent antimicrobial spectrum and thus have been energeticallystudied as a highly useful β-lactam agent.

In WO 02/42312, the present inventors have reported their finding thatcarbapenem derivatives having a7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazole groupat the 2-position on the carbapenem ring, that is, compounds of formula(A), have high antimicrobial activity against Gram-positive bacteria andGram-negative bacteria including MRSA (methicillin resistantStaphylococcus aureus), PRSP (penicillin resistant Streptococcuspneumoniae), Haemophilus influenzae, and β-lactamase producing bacteria,and, at the same time, have high stability against DHP-1 (kidneydehydropeptidase-1). In this publication, a production process shown inscheme A below is disclosed as a production process of such derivatives.

wherein R¹ represents a hydrogen atom or represents a protective groupof hydroxyl; R² represents a protective group of carboxyl; and L³represents a leaving group.

According to this production process, the compound of formula (A) isproduced by reacting a compound of formula (i) with a compound offormula (ii) in the presence of a palladium catalyst, a phosphineligand, and an additive to give a compound of formula (iii),subsequently reacting the compound of formula (iii) with a compound offormula (Iv) to give a compound of formula (v), and then deprotectingthe compound of formula (v).

However, the compound of formula (ii) used in this process and reagentssuch as a trialkyltin chloride used for preparing this compound belongto organotin compounds and are known to be highly toxic. Further, thepalladium catalyst and the phosphine ligand used in the reaction of thecompound of formula (i) with the compound of formula (ii) are generallyexpensive. Therefore, a process which can produce the carbapenemderivatives of formula (A) in a highly safe and more cost-effectivemanner has been desired.

SUMMARY OF THE INVENTION

The present inventors have now succeeded in producing compoundsrepresented by formula (1), which will be described later, as asynthetic intermediate for carbapenem derivatives represented by formula(A). Specifically, compounds represented by formula (2) which will bedescribed later could be produced as a precursor of carbapenemderivatives represented by formula (A) by treating the compoundrepresented by formula (1) under conditions, which can form a carbapenemring, to form a carbapenem ring through a ring-closing reaction. Theproduction process using the compound of formula (1) does not need touse any highly toxic compound such as the organotin compound and doesnot substantially use expensive chemicals such as a palladium catalyst.The present invention has been made based on such finding.

Accordingly, an object of the present invention is to provide aproduction process, which can produce carbapenem derivatives representedby formula (A) in an efficient, safe and cost-effective manner, and asynthetic intermediate for use in said production process.

According to the present invention, there is provided a compoundrepresented by formula (1):

wherein

R¹ represents a hydrogen atom or a protective group of hydroxyl,

R² represents a hydrogen atom, a protective group of carboxyl, or ananion in a carboxylate anion,

Z¹ and Z² together represent an oxygen atom or a protective group ofcarbonyl, or

one of Z¹ and Z² represents a hydrogen atom and the other representshydroxyl or protected hydroxyl,

Y represents an oxygen atom or group P(R³)₃,

wherein R³s, which may be the same or different, represent

C1-6 alkyl optionally substituted by a halogen atom, or

aryl optionally substituted by a halogen atom or C1-6 alkyl in which thealkyl group may be substituted by a halogen atom.

According to another aspect of the present invention, there is provideda process for producing a compound represented by formula (1) wherein Yrepresents group P(R³)₃, said process comprising the step of

reacting a reaction mixture, prepared by treating a compound of formula(4′) with a Grignard reagent, with a compound of formula (5):

wherein

Z¹¹ and Z¹² together represent an oxygen atom or a protective group ofcarbonyl, or

one of Z¹¹ and Z¹² represents a hydrogen atom and the other representsprotected hydroxyl, and

X represents a halogen atom; and

wherein

R¹¹ represents a protective group of hydroxyl,

R² and R³ are as defined in formula (1), and

R⁴ represents

optionally substituted C1-6 alkyl, or

aryl optionally substituted by a group selected from the groupconsisting of a halogen atom, optionally substituted C1-6 alkyl,optionally substituted C1-6 alkoxy, and —NR⁵R⁶,

wherein R⁵ and R⁶, which may be the same or different, represent C1-6alkyl, or R⁵ and R⁶ together represent —(CH₂)_(n)— wherein n is aninteger of 2 to 6.

In a preferred embodiment of the present invention, the process forproducing a compound represented by formula (1), wherein Y representsgroup P(R³)₃, further comprises preparing the compound of formula (4′)by steps (c) and (d):

(c) formylating a compound of formula (14) with a Vilsmeyer complex togive a compound of formula (18):

wherein X represents a halogen atom, and

wherein X represents a halogen atom, and

(d) reacting the compound of formula (18) with a 3-metallopyridine offormula (19) to give a compound of formula (4′) in which one of Z¹¹ andZ¹² represents a hydrogen atom and the other represents hydroxyl, andeither protecting hydroxyl in this compound, or oxidizing hydroxyl inthis compound and protecting carbonyl in the resultant compound, to givethe compound of formula (4′):

wherein M represents lithium, MgBr, or MgI.

In a preferred embodiment of the present invention, the process forproducing a compound represented by formula (1), wherein Y representsgroup P(R³)₃, further comprises preparing the compound of formula (14)by steps (a) and (b):

(a) reacting a compound of formula (15) with a halogenating agent togive a compound of formula (16) and formulating the amino group in thecompound of formula (16) optionally after removing the protective group,to give a compound of formula (17):

wherein

R⁸ represents a hydrogen atom, or a protective group of amino and

X represents a halogen atom, and

(b) reacting the compound of formula (17) with a dehydrating agent forcyclization to give a compound of formula (14).

According to still another aspect of the present invention, there isprovided a process for producing a compound represented by formula (1)wherein Y represents an oxygen atom, said process comprising the step of

reacting a compound of formula (8) with a compound of formula (9) in thepresence of a base:

wherein

R⁷ represents a hydrogen atom, or a protective group of amino,

R¹, R², Z¹ and Z² are as defined in formula (1), and

L² represents a leaving group.

In a preferred embodiment of the present invention, the process forproducing a compound represented by formula (1), wherein Y represents anoxygen atom, further comprises preparing the compound of formula (8) bystep (f):

(f) reacting a compound, prepared by treating a compound of formula (6′)with an alkali metal base, or a base and a monovalent to tetravalentmetal compound, with a compound of formula (7), and optionally removinga protective group and/or introducing a protective group and/orconducting oxidization to give a compound of formula (8):

wherein

Z¹¹ and Z¹² together represent an oxygen atom, or a protective group ofcarbonyl, or

one of Z¹¹ and Z¹² represents a hydrogen atom and the other representsprotected hydroxyl; and

wherein

R¹¹ represents a protective group of hydroxyl,

R⁷ represents a hydrogen atom or a protective group of amino, and

L¹ represents a leaving group.

In a preferred embodiment of the present invention, the process forproducing a compound represented by formula (1), wherein Y represents anoxygen atom, further comprises preparing a compound of formula (6′) bysteps (c), (d) and (e):

(c) formylating a compound of formula (14) with a Vilsmeyer complex togive a compound of formula (18):

wherein X represents a halogen atom,

(d) reacting the compound of formula (18) with a 3-metallopyridine offormula (19) to give a compound of formula (4′) wherein one of Z¹¹ andZ¹² represents a hydrogen atom and the other represents hydroxyl, andeither protecting hydroxyl in this compound, or oxidizing hydroxyl inthis compound and protecting carbonyl in the resultant compound, to givea compound of formula (4′):

wherein M represents lithium, MgBr, or MgI, and

(e) reacting a compound, prepared by treating the compound of formula(4′) with a Grignard reagent, with a propionic acid derivative to give acompound of formula (6′).

In a preferred embodiment of the present invention, the process forproducing a compound represented by formula (1), wherein Y represents anoxygen atom, further comprises preparing a compound of formula (14) bysteps (a) and (b):

(a) reacting a compound of formula (15) with a halogenating agent togive a compound of formula (16), which, optionally after the removal ofa protective group, undergoes formylation of amino to give a compound offormula (17):

wherein

R⁸ represents a hydrogen atom, or a protective group of amino, and

X represents a halogen atom, and

(b) reacting the compound of formula (17) with a dehydrating agent forcyclization to give a compound of formula (14).

According to a further aspect of the present invention, there isprovided a process for producing a compound represented by formula (1),wherein Y represents group P(R³)₃, said process comprising the steps of

halogening hydroxyl in a compound of formula (11), prepared by reactinga compound of formula (8) with a compound of formula (10) or itsreactive equivalent, with a halogenating agent, and reacting theresultant compound with a compound of formula (13):

wherein

R¹¹ represents a protective group of hydroxyl,

R¹, R², and R³ are as defined in formula (1),

R⁷ represents a hydrogen atom,

Z¹ and Z² together represent an oxygen atom, or a protective group ofcarbonyl, or,

one of Z¹ and Z² represents a hydrogen atom and the other representshydroxyl or protected hydroxyl,

Z¹¹ and Z¹² together represent an oxygen atom, or a protective group ofcarbonyl, or

one of Z¹¹ and Z¹² represents a hydrogen atom and the other representsprotected hydroxyl.

According to another aspect of the present invention, there is provideda process for producing a compound of formula (2), said processcomprising the steps of

treating a compound of formula (1) under conditions, which can form acarbapenem ring, to form a carbapenem ring through a ring-closingreaction and optionally conducting the removal of a protective groupand/or oxidation:

wherein

R¹ represents a hydrogen atom, or represents a protective group ofhydroxyl,

R represents a hydrogen atom, a protective group of carboxyl, or ananion in a carboxylate anion,

Z¹ and Z² together represent an oxygen atom, or a protective group ofcarbonyl, or

one of Z¹ and Z² represents a hydrogen atom and the other representshydroxyl or protected hydroxyl.

According to still another aspect of the present invention, there isprovided a process for producing a compound of formula (A), comprisingthe step of

preparing the compound of formula (2) from the compound of formula (1)by the above process for producing a compound of formula (2):

In a preferred embodiment of the present invention, the process forproducing a compound represented by formula (A) further comprises thestep of reacting the compound of formula (2) with a compound of formula(Iv) to give a compound of formula (3):

wherein

L³ represents a leaving group,

R¹ represents a hydrogen atom, or represents a protective group ofhydroxyl, and

R represents a hydrogen atom, a protective group of carboxyl, or ananion in a carboxylate anion.

In a preferred embodiment of the present invention, the process forproducing a compound represented by formula (A) further comprises thestep of removing the protective group in the compound of formula (3) bya deprotection reaction to give the compound of formula (A).

In a further preferred embodiment of the present invention, the processfor producing a compound of formula (A) further comprises the step ofpreparing the compound of formula (1) by one of the production processesof the compound of formula (1).

According to the present invention, there is also provided a compoundrepresented by formula (4):

wherein

Z¹ and Z² together represent an oxygen atom, or a protective group ofcarbonyl, or

one of Z¹ and Z² represents a hydrogen atom and the other representshydroxyl or protected hydroxyl, and

X represents a halogen atom.

According to the present invention, there is also provided a compoundrepresented by formula (6):

wherein

Z¹ and Z² together represent an oxygen atom, or a protective group ofcarbonyl, or

one of Z¹ and Z² represents a hydrogen atom and the other representshydroxyl or protected hydroxyl.

According to the present invention, there is further provided a compoundrepresented by formula (8):

wherein

R¹ represents a hydrogen atom, or represents a protective group ofhydroxyl,

Z¹ and Z² together represent an oxygen atom, or a protective group ofcarbonyl, or

one of Z¹ and Z² represents a hydrogen atom and the other representshydroxyl or protected hydroxyl, and

R⁷ represents a hydrogen atom, or a protective group of amino.

According to the present invention, there is also provided a compoundrepresented by formula (14a):

In a further aspect of the present invention, there is provided use of acompound of formula (1) according to the present invention, as asynthetic intermediate for the production of an antimicrobial agent.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl” as used herein as a group or a part of a group meansstraight chain, branched chain, or cyclic, either alone or incombination, alkyl, unless otherwise specified. “C1-6,” for example, in“C1-6 alkyl” means that the alkyl group has 1 to 6 carbon atoms.

“C1-6 alkyl” is preferably C1-4 alkyl, more preferably C1-3 alkyl.Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl,i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl.

The term “alkoxy” as used herein as a group or a part of a group meansstraight chain, branched chain, or cyclic, either alone or incombination, alkoxy.

“C1-6 alkoxy” is preferably C1-4 alkoxy, more preferably C1-3 alkoxy.Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, s-butoxy, and t-butoxy.

The term “alkenyl” as used herein as a group or a part of a group meansstraight chain, branched chain, or cyclic, either alone or incombination, alkenyl. Preferably, alkenyl is straight chain or branchedchain alkenyl. The number of double bonds contained in the alkenyl partin the group is not particularly limited, and the double bond may be inZ-configuration or E-configuration. Alkenyl is, for example, C2-6alkenyl. “C2-6 alkenyl” is preferably C2-5 alkenyl, more preferably C2-4alkenyl. Examples of alkenyl include vinyl, allyl, propenyl,isopropenyl, butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl,2-methylallyl, pentenyl, 2-pentenyl, cyclopentenyl, hexenyl, 2-hexenyl,and cyclohexenyl.

The term “halogen atom” as used herein means a fluorine, chlorine,bromine, or iodine atom. Preferably, the halogen atom is a chlorine,bromine, or iodine atom.

The term “aryl” as used herein as a group or a part of a group means asix- to fourteen-membered monocyclic to tricyclic aromatic carbocylicring. Preferably, aryl is a five- to seven-membered aromatic monocycliccarbocyclic ring or an eight- to twelve-membered aromatic bicycliccarbocyclic ring. Examples of aryl include phenyl, 1-naphthyl,2-naphthyl, biphenyl, 2-anthrylnaphthy. In the present invention, arylis particularly preferably phenyl.

The term “aralkyl” as used herein as a group or a part of a group meansC1-6 alkyl substituted by the above aryl. Here in the alkyl or arylpart, one or more hydrogen atoms on the group may be substituted by oneor more substituents which may be the same or different. Examples ofsubstituents include nitro, a halogen atom, C1-6 alkyl, and C1-6 alkoxy.The C1-6 alkyl part in the aralkyl group is preferably C1-4 alkyl, morepreferably C1-3 alkyl, still more preferably C1-2 alkyl. Examples ofaralkyl include benzyl, diphenylmethyl, trityl, phenethyl,4-methoxybenzyl, 2-nitrobenzyl, and 4-nitrobenzyl (pNB).

The term “acyl” that is used herein as a group or a part of a groupmeans straight chain, branched chain, or cyclic acyl. The acyl group maybe, for example, include C1-8 acyl, preferably C1-6 acyl, morepreferably C1-4 acyl. Examples of acyl include formyl, alkylcarbonyl,aralkylcarbonyl, arylcarbonyl, specifically, for example, formyl,acetyl, propionyl, butyryl, toluoyl, anisoyl, and benzoyl.

The expression “optionally substituted” alkyl as used herein means thatone or more hydrogen atoms on the alkyl group are optionally substitutedby one or more substituents which may be the same or different. It willbe apparent to a person having ordinary skill in the art that themaximum number of substituents may be determined depending upon thenumber of substitutable hydrogen atoms on the alkyl group. This is trueof alkoxy, alkenyl or other groups.

The protective group of hydroxyl which may be represented by R¹ or R¹¹is not particularly limited so far as the protective group of hydroxylis usually used in the synthesis of carbapenem derivatives and may beproperly selected by a person having ordinary skill in the art. Suchprotective groups of hydroxyl include, for example, silyl such ast-butyldimethylsilyl, trimethylsilyl, and triethylsilyl; and oxycarbonylsuch as 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, andallyloxycarbonyl. Preferably, the protective group of hydroxyl which maybe represented by R¹ or R¹¹ is silyl such as t-butyldimethylsilyl,trimethylsilyl, or triethylsilyl, more preferably t-butyldimethylsilylor triethylsilyl.

R¹ or R¹¹ is preferably selected from the group consisting of a hydrogenatom, t-butyldimethylsilyl, trimethylsilyl, and triethylsilyl, morepreferably selected from the group consisting of a hydrogen atom andt-butyldimethylsilyl.

The protective group of carboxyl which may be represented by R² or R isnot particularly limited and may be any protective group so far as it iswell known to a person having ordinary skill in the art as a protectivegroup of carboxyl. Preferably, the protective group of carboxyl iseasily removable. Such protective groups of carboxyl include, forexample, aralkyl such as 4-nitrobenzyl (pNB), 4-methoxybenzyl, anddiphenylmethyl; alkenyl such as allyl; and silyl such ast-butyldimethylsilyl. Preferably, the protective group of carboxylrepresented by R² or R is allyl, 4-nitrobenzyl, 4-methoxybenzyl, ordiphenylmethyl, more preferably allyl or 4-nitrobenzyl.

R² or R may represent an anion in a carboxylate anion (—COO⁻). In thiscase, the carboxylate anion may be in the form of a salt. The salt is apharmaceutically acceptable salt. Such pharmaceutically acceptable saltsinclude inorganic salts such as salts with metals such as lithium,sodium, potassium, calcium, or magnesium, ammonium salts, or salts withorganic bases such as triethylamine or diisopropylethylamine.

R² or R is preferably selected from the group consisting of a hydrogenatom, an anion in a carboxylate anion, 4-nitrobenzyl, 4-methoxybenzyl,diphenylmethyl, allyl, and t-butyldimethylsilyl, more preferablyselected from the group consisting of allyl, 4-nitrobenzyl, and4-methoxybenzyl.

In one preferred embodiment of the present invention, R represents ahydrogen atom, an anion in a carboxylate anion, or a protective group ofcarboxyl, and R² represents an easily removable protective group ofcarboxyl.

When Y represents group P(R³)₃, the “C1-6 alkyl optionally substitutedby a halogen atom” which may be represented by R³ may be, for example,chlorinated alkyl, and specific examples thereof include methyl, ethyl,propyl, n-butyl, t-butyl, chloromethyl, and dichloroethyl. Preferred arepropyl, n-butyl, and t-butyl.

The “aryl optionally substituted by a halogen atom or C1-6 alkyl,optionally substituted by a halogen atom” which may be represented by R³may be, for example, aryl optionally substituted by a halogen atom orunsubstituted C1-6 alkyl. Preferably, R³ is 4-fluorophenyl,o-methylphenyl, m-methylphenyl, p-methylphenyl, or unsubstituted phenyl,more preferably unsubstituted phenyl.

Y preferably represents an oxygen atom or group P(C₆H₅)₃.

The protective group of carbonyl which can be formed by combining Z¹ andZ² together is not particularly limited and may be any protective groupof carbonyl so far as it is well known to a person having ordinary skillin the art. Preferably, the protective group of carbonyl is easilyremovable. Such protective groups of carbonyl include, for example,dialkoxy such as dimethoxy or diethoxy; alkylenedioxy such asethylenedioxy or trimethylenedioxy; alkylenedithio such asethylenedithio or trimethylenedithio; hydrazone such asdimethylhydrazone or phenylhydrazone; and oxime, O-methyloxime,O-benzyloxime, and methylene. Preferably, the protective group ofcarbonyl is dialkoxy such as dimethoxy or diethoxy, or hydrazone such asdimethylhydrazone.

When one of Z¹ and Z² represents a hydrogen atom, the protective groupof protected hydroxyl which may be represented by the other group is notparticularly limited and may be any protective group of hydroxyl so faras it is well known as the protective group to a person having ordinaryskill in the art. Such protective groups of hydroxyl include, forexample, silyl such as t-butyldimethylsilyl, trimethylsilyl, ortriethylsilyl; oxycarbonyl such as 4-nitrobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, or allyloxycarbonyl; and aralkyl such asbenzyl or 4-methoxybenzyl. Preferably, the protected hydroxyl which maybe represented by R¹ or R¹¹ is hydroxyl protected by silyl such ast-butyldimethylsilyl, trimethylsilyl, or triethylsilyl, more preferablyhydroxyl protected by trimethylsilyl or triethylsilyl.

Preferably, Z¹ and Z² together represent a group selected from the groupconsisting of an oxygen atom, dimethoxy, diethoxy, anddimethylhydrazone. Alternatively, one of Z¹ and Z² represents a hydrogenatom, and the other represents hydroxyl, or represents hydroxylprotected by a group selected from the group consisting oft-butyldimethylsilyl, trimethylsilyl, and triethylsilyl.

More preferably, Z¹ and Z² together form an oxygen atom, dimethoxy,diethoxy, or dimethylhydrazone, or alternatively one of Z¹ and Z²represents a hydrogen atom and the other represents hydroxyl protectedby triethylsilyl.

In the “optionally substituted C1-6 alkyl” which may be represented byR⁴, for example, a halogen atom such as a chlorine atom or a bromineatom may be mentioned as the substituent. Accordingly, the “optionallysubstituted C1-6 alkyl” which may be represented by R⁴ is preferably“C1-6 alkyl optionally substituted by a halogen atom.” Specific examplesthereof include methyl, ethyl, propyl, n-butyl, t-butyl,2-chloro-1,1-dimethylethyl, 2-chloroethyl, and 1-bromoisobutyl. The“optionally substituted C1-6 alkyl” is more preferably t-butyl and2-chloro-1,1-dimethylethyl.

In the “aryl optionally substituted by a group selected from the groupconsisting of a halogen atom, optionally substituted C1-6 alkyl,optionally substituted C1-6 alkoxy, and —NR⁵R⁶” which may be representedby R⁴, the aryl group is preferably phenyl.

R⁵ and R⁶, which may be the same or different, represent C1-6 alkyl, oralternatively R⁵ and R⁶ together represent —(CH₂)_(n)— wherein n is aninteger of 2 to 6, preferably an integer of 4 to 6.

“Optionally substituted C1-6 alkyl” as a substituent for “aryl” whichmay be represented by R⁴ is preferably “a halogen atom, C1-6 alkyl, orC1-6 alkyl optionally substituted by C1-6 alkoxy.” The “optionallysubstituted C1-6 alkoxy” as the substituent is preferably “a halogenatom, C1-6 alkyl, or C1-6 alkoxy optionally substituted by C1-6 alkoxy.”

In aryl which may be represented by R⁴, when one or more hydrogen atomsthereof are substituted by a substituent, specific examples of thesubstituent include halogen atoms such as chlorine, bromine, andfluorine atoms; straight chain alkyl such as methyl, ethyl, andn-propyl; branched chain alkyl such as isopropyl and t-butyl; straightchain alkoxy such as methoxy, ethoxy, and isopropyloxy; N,N-di(C1-6alkyl)amino such as N,N-dimethylamino and N,N-diethylamino; and three-to seven-membered cyclic alkylamino such as 1-pyrrolidinyl and1-piperidinyl. Preferred substituents include C1-6 alkoxy andN,N-di(C1-6 alkyl)amino or three- to seven-membered cyclic alkylamino.

Aryl which may be represented by R⁴ is preferably unsubstituted phenyl,2-chlorophenyl, 2-methylphenyl, 3,4-dimethylphenyl, 2-methoxyphenyl,4-methoxyphenyl, 2-ethoxyphenyl, 4-isopropyloxyphenyl,4-(N,N-dimethylamino)phenyl, or 4-(N,N-diethylamino)phenyl. Morepreferably, aryl which may be represented by R⁴ is 4-methoxyphenyl,4-isopropyloxyphenyl, 4-(N,N-dimethylamino)phenyl or4-(N,N-diethylamino)phenyl.

The protective group of amino which may be represented by R⁷ and R⁸ isnot particularly limited and may be any protective group of amino so faras the protective group is well known to a person having ordinary skillin the art. Protective groups of amino usable herein include, forexample, acyl such as formyl, alkylcarbonyl (such as acetyl), andarylcarbonyl (such as benzoyl); aralkyl such as benzyl; oxycarbonyl suchas alkylcarbonyl (such as t-butoxycarbonyl), and arylcarbonyl (such asbenzyloxycarbonyl); sulfonyl such as alkylsulfonyl (such asmethanesulfonyl), and arylsulfonyl (such as benzensulfonyl); and silylsuch as trialkylsilyl (such as trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl). Preferred are formyl, t-butoxycarbonyl, trimethylsilyl,triethylsilyl and the like.

Examples of the leaving group represented by L¹ include acyloxy such asalkylcarbonyloxy (such as acetoxy) or arylcarbonyloxy (such asbenzoyloxy); arylsulfonyloxy such as benzensulfonyloxy; alkylsulfonylsuch as methanesulfonyl; alkanoylthio such as acetylthio; alkylthio suchas methylthio; alkylsulfinyl such as methylsulfinyl; arylsulfinyl suchas benzenesulfinyl; alkylsulfonyl such as methanesulfonyl; arylsulfonylsuch as benzensulfonyl; and halogen atoms such as chlorine, bromine, andiodine atoms. The leaving group represented by L¹ is preferablymethylthio, acetylthio, a chlorine atom, or acetoxy, more preferablyacetoxy.

Examples of the leaving group represented by L² include halogen atomssuch as chlorine, bromine, and iodine atoms; alkylsulfonyloxy such asmethanesulfonyloxy; and arylsulfonyloxy such as benzensulfonyloxy.Preferably, the leaving group represented by L² is methanesulfonyloxy ora chlorine atom, more preferably a chlorine atom or the like.

Examples of the leaving group represented by L³ include halogen atomssuch as chlorine, bromine, and iodine atoms; alkylsulfonyloxy optionallysubstituted by a halogen atom, such as methanesulfonyloxy,benzensulfonyloxy, —OSO₂CF₃, or —OSO₂PhCH₃, and arylsulfonyloxyoptionally substituted by alkyl. Preferably, the leaving grouprepresented by L³ is —OSO₂CF₃ or an iodine atom, more preferably aniodine atom.

X represents a halogen atom, for example, a chlorine, bromine, or iodineatom, preferably a bromine or iodine atom, more preferably a bromineatom.

M represents lithium, MgBr, or MgI, preferably MgBr.

In one preferred embodiment of the present invention,

R¹ represents a hydrogen atom, or represents a protective group ofhydroxyl,

R represents a hydrogen atom, an anion in a carboxylate anion, or aprotective group of carboxyl,

R² represents a protective group of carboxyl,

X represents a bromine or iodine atom,

Y represents an oxygen atom or group P(C₆H₅)₃, and

Z¹ and Z² together represent an oxygen atom or an easily removableprotective group of carbonyl, or alternatively one of Z¹ and Z²represents a hydrogen atom and the other represents protected hydroxyl.

In one preferred embodiment of the present invention, in formula (1),

R¹ represents a hydrogen atom, or represents a protective group ofhydroxyl,

R² represents a protective group of carboxyl,

Y represents an oxygen atom or group P(C₆H₉)₃,

Z¹ and Z² together represent an oxygen atom or a protective group ofcarbonyl, or alternatively one of Z¹ and Z² represents a hydrogen atomand the other represents protected hydroxyl.

In another preferred embodiment of the present invention, in formula(1),

R¹ represents a hydrogen atom or a protective group of hydroxyl,

R² represents an easily removable protective group of carboxyl,

Z¹ and Z² together represent an oxygen atom or an easily removableprotective group of carbonyl, or one of Z¹ and Z² represents a hydrogenatom and the other represents hydroxyl or protected hydroxyl, and

Y represents an oxygen atom or group P(R³)₃,

wherein R³s, which may be the same or different, represent

C1-6 alkyl optionally substituted by a halogen atom, or

aryl optionally substituted by a halogen atom or C1-6 alkyl in which thealkyl group may be substituted by a halogen atom.

Specific examples of compounds represented by formula (1) include:

-   (3S,4R)-1-allyloxyoxalyl-3-[(1R)-1-(tert-butyldimethyl    silyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonyl    imidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one (compound of    Example 23);-   (3S,4R)-1-allyloxyoxalyl-3-[(1R)-1-hydroxyethyl)-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one    (compound of Example 25);-   (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenyl    phosphoranylidene)methyl]azetidin-2-one (compound of Example 27);-   (3S,4R)-3-[(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyl-oxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-one    (compound of Example 29);-   (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one    (compound of Example 31);-   (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-dimethoxy-(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one    (compounds of Examples 32 to 35);-   (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonyl-imidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one    (compounds of Example 36 etc.);-   (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-diethoxy-(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one    (compound of Example 37);-   (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one    (compound of Example 40); and-   (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]-1-[4-nitrobenzyloxycarbonyl    (triphenylphosphoranylidene)methyl]azetidin-2-one (compound of    Example 42).

Preferably, compounds represented by formula (1) include:

-   (3S,4R)-1-allyloxyoxalyl-3-[(1R)-1-(tert-butyldimethyl    silyl-oxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one    (compound of Example 23);-   (3S,4R)-1-allyloxyoxalyl-3-[(1R)-1-hydroxyethyl)-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one    (compound of Example 25);-   (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one    (compound of Example 31);-   (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-dimethoxy-(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one    (compounds of Examples 32 to 35);-   (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)    methyl]-3-[(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridine-3-yl)carbonyl-imidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one    (compound of Example 36 etc.); and-   (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-diethoxy-(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one    (compound of Example 37).

More preferably, compounds represented by formula (1) include:

-   (3S,4R)-1-allyloxyoxalyl-3-[(1R)-1-(tert-butyldimethyl    silyl-oxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one    (compound of Example 23);-   (3S,4R)-1-allyloxyoxalyl-3-[(1R)-1-hydroxyethyl)-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]-azetidin-2-one    (compound of Example 25);-   (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-dimethoxy-(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one    (compounds of Examples 32 to 35); and-   (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridine-3-yl)carbonyl-imidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one    (compounds of Example 36 etc.).

Specific examples of preferred compounds represented by formula (3)include:

-   2-bromo-7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole;-   2-bromo-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole;-   2-bromo-7-diethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole; and-   2-bromo-7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazole.

Specific examples of preferred compounds represented by formula (6)include:

-   2-propionyl-7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole;-   2-propionyl-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole;    and-   2-propionyl-7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazole.

Specific examples of preferred compounds represented by formula (8)include:

-   (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one;-   (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one;-   (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one;-   (3S,4R)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one;    and-   (3S,4R)-3-[(1R)-1-(triethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

Scheme for Production of Compounds of Formula (1) and Compounds ofFormula (A)

The process for the production of compounds of formula (1) according tothe present invention and the process for the production of compounds offormula (A) are as shown in scheme B below.

(I) Production of Compounds of Formula (14)

Compounds of formula (14) can be synthesized by the process shown inscheme I below.

wherein R⁸ represents a hydrogen atom or a protective group of amino;and X represents a halogen atom, preferably a bromine atom.

In the present invention, the compound of formula (14) can be producedby steps (a) and (b) below as shown in scheme I:

(a) the step of reacting the compound of formula (15) with ahalogenating agent to give a compound of formula (16), optionallyremoving the protective group, and then formulating the amino group togive a compound of formula (17); and

(b) the step of reacting the compound of formula (17) with a dehydratingagent for cyclization, to give a compound of formula (14).

Specifically, according to the process shown in scheme I, in step I-1,the compound of formula (16) is produced by reacting the compound offormula (15) with a halogenating agent. In step I-2, the compound offormula (17) is produced by, when R⁸ represents a hydrogen atom or aprotective group other than formyl, converting R⁸ to formyl, or, ifnecessary, removing the protective group in the compound of formula(16), and then formylating the amino group. Subsequently, in step I-3,the compound of formula (14) is produced by reacting the compound offormula (17) with a hydrating agent for cyclization.

When X represents a bromine atom, formula (14) may be represented byformula (14a):

(Step I-1)

The compound of formula (15) in step I-1 may be a commercially availableproduct or alternatively may be synthesized by a conventional method.For example, the compound of formula (15) may be synthesized by themethod described in Japanese Patent Laid-Open Publication No.311071/1996.

In this step, the compound of formula (15) is halogenated. The compoundof formula (16) may be produced by reacting the compound of formula (15)with a halogenating agent in a solvent inert to the reaction in thepresence of a base and an additive.

The solvent used in step I-1 is not particularly limited and may beproperly selected by a person having ordinary skill in the art so far asthe solvent is inert to the reaction in this step. Specific examples ofsolvents include chloroform, methylene chloride, ethyl alcohol, methylalcohol, tetrahydrofuran, dioxane, acetonitrile, and water. They may beused as a mixed solvent composed of two or more solvents. Preferably,the solvent may be a mixed solvent composed of tetrahydrofuran andwater.

Usable bases include, for example, sodium hydrogencarbonate, sodiumcarbonate, sodium hydroxide, and sodium acetate. Preferably, the base issodium hydroxide.

Additives include, for example, salts such as sodium chloride and sodiumbromide; and buffering agents such as sodium dihydrogenphosphate,disodium hydrogen phosphate, acetic acid, and sodium acetate.Preferably, the additive is sodium bromide or sodiumdihydrogenphosphate. The amount of the additive used is preferably 5 to50 times by weight that of the compound of formula (15).

The halogenating agent may be conventional. Preferred are chlorinatingagents, brominating agents, iodinating agents and the like. Thehalogenating agent is more preferably a brominating agent. Brominatingagents include, for example, bromine and N-bromosuccinimide. Morepreferably, the halogenating agent is bromine. The amount of thehalogenating agent used is preferably 5 to 10 molar equivalents relativeto the compound of formula (15).

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range of 0°C. to the reflux temperature of the solvent used. The reaction time mayvary depending upon the solvent used, the reaction temperature and thelike. In general, however, the reaction time is 10 min to 24 hr.

The resultant compound of formula (16) may be subjected to conventionalpost treatment. Here the conventional post treatment is well known to aperson having ordinary skill in the art, and examples thereof includequenching (stopping of reaction) and extraction. Further, isolation andpurification may be carried out by optionally applying conventionalmethods such as precipitation, crystallization, gel filtration, andcolumn chromatography on silica gel.

(Step I-2)

In step I-2, the compound of formula (17) is produced by, when R⁸ in thecompound of formula (16) represents a hydrogen atom or a protectivegroup other than formyl, converting R⁸ to formyl, or optionally removingthe protective group of the compound of formula (16), and thenformylating the amino group.

The reaction for removing the protective group of amino may varydepending upon the type of the protective group. However, this reactionmay be carried out by using as reference a reaction for removing theprotective group of amino in conventional organic synthetic chemistry.For example, when the protective group of amino, R⁸, in the compound offormula (16) is t-butoxycarbonyl, t-butoxycarbonyl as the protectivegroup can be removed by reacting the compound of formula (16) in asolvent inert to the reaction (for example, methanol, ethanol, methylenechloride, chloroform, tetrahydrofuran, dioxane, toluene, hexane, oranisole) at a temperature in a range of −20° C. to the refluxtemperature of the solvent used, using an acid such as hydrochloricacid, sulfuric acid, methanesulfonic acid, or trifluoroacetic acidand/or a Lewis acid such as aluminum trichloride, bromocatecholborane,or trimethylsilyl trifluoromethanesulfonate in an amount of 0.1 to 100molar equivalents relative to the compound of formula (16) for 10 min to24 hr.

The reaction for formylating the amino group may be carried out by usingas reference a reaction for formylating the amino group in theconventional organic synthetic chemistry. For example, the amino groupmay be formylated, for example, by, when R⁸ in the compound of formula(16) represents a hydrogen atom, using the compound of formula (16) assuch, or reacting the compound of formula (16) for removing theprotective group of amino, and then reacting the compound in a solventinert to the reaction (for example, methylene chloride, chloroform,water, dimethylformamide, tetrahydrofuran, dioxane, toluene, or hexane)or without using any solvent at a temperature in a range of −20° C. tothe reflux temperature of the solvent used, using a formic ester such asethyl formate or n-propyl formate, a mixed acid anhydride such as formicacid acetic anhydride or formic acid pivalic acid anhydride, or anactive ester such as 4-nitrophenyl formate, in an amount of 1 to 100molar equivalents relative to the compound of formula (16) for 10 min to24 hr.

The compound of formula (17) may be subjected to conventional posttreatment. Further, isolation and purification may be carried out byoptionally applying conventional methods such as precipitation,crystallization, gel filtration, and column chromatography on silicagel.

(Step I-3)

Step I-3 is a cyclization reaction of the compound of formula (17) whichmay be carried out, for example, by the method described in JapanesePatent Laid-Open Publication No. 311071/1996. In step I-3, the compoundof formula (14) may be produced by reacting the compound of formula (17)with a dehydrating agent in a solvent inert to the reaction or in theabsence of any solvent for cyclization.

The solvent used in step I-3 is not particularly limited and may beproperly selected by a person having ordinary skill in the art, so faras the solvent is inert to the reaction. Specific examples thereofinclude benzene, toluene, xylene, methylene chloride, chloroform, and1,2-dichloroethane. The solvent is preferably toluene.

Dehydrating agents include, for example, phosphorus oxychloride,phosphorus oxybromide, phosphorus pentachloride, polyphosphoric acid,sulfuric acid, thionyl chloride, trifluoroacetic anhydride, andtrifluoromethansulfonic anhydride. The dehydrating agent is preferablyphosphorus oxychloride. The amount of the dehydrating agent used ispreferably 1 to 100 molar equivalents relative to the compound offormula (17).

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range of−20° C. to the reflux temperature of the solvent used. The reaction timemay vary depending upon the solvent used, the temperature of thereaction and the like. In general, however, the reaction time is 10 minto 24 hr.

The compound of formula (14) may be subjected to conventional posttreatment. Further, isolation and purification may be carried out byoptionally applying conventional methods such as precipitation,crystallization, gel filtration, and column chromatography on silicagel.

(II) Production of Compounds of Formula (4) and Formula (6)

Compounds of formula (4) and formula (6) may be synthesized, forexample, by the process shown in scheme II below.

wherein X, Z¹¹ and Z¹² are as defined above.

In the present invention, as shown in scheme II, the compound of formula(4′) may be produced by steps of (c) and (d) below:

(c) the step of formylating the compound of formula (14) using aVilsmeyer complex to give the compound of formula (18).

(d) the step of reacting the compound of formula (18) with a3-metallopyridine of formula (19) to give a compound (a compound offormula (4a)) of formula (4′) in which one of Z¹¹ and Z¹² represents ahydrogen atom and the other represents hydroxyl, and protecting hydroxylin this compound, or oxidizing hydroxyl in this compound and protectingthe resultant carbonyl to give the compound of formula (4′):

wherein M represents lithium, MgBr, or MgI.

When the compound of formula (6′) is necessary, this compound can beproduced by further carrying out step (e):

(e) the step of reacting a compound, obtained by treating the compoundof formula (4′) with a Grignard reagent, with a propionic acidderivative to give a compound of formula (6′).

(Step II-1)

Step II-1 is a formylation reaction of the compound of formula (14)which may be carried out, for example, by the method described inJapanese Patent Laid-Open Publication No. 311071/1996. In step II-1, thecompound of formula (18) may be produced by reacting the compound offormula (14) with separately prepared Vilsmeyer complex in a solventinert to the reaction.

The solvent used in step II-1 is not particularly limited and may beproperly selected by a person having ordinary skill in the art, so faras the solvent is inert to the reaction. Specific examples thereofinclude methylene chloride, chloroform, 1,2-dichloroethane,dimethylformamide, and nitrobenzene. The solvent is preferably methylenechloride.

The Vilsmeyer complex refers to a reactant used in a formylationreaction well known to a person having ordinary skill in the art, thatis, a Vilsmeyer's reaction and may be properly selected by a personhaving ordinary skill in the art. The Vilsmeyer complex may be amethyleneiminium compound prepared, for example, by reactingN,N-dimethylformamide, N-methylformanilide, N-formylmorpholine, orN,N-diisopropylformamide, with a halogenating reagent such as phosphorusoxychloride, phosgene, oxalyl chloride, or thionyl chloride. The amountof the Vilsmeyer complex used is preferably 1 to 10 molar equivalentsrelative to the compound of formula (14).

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range of−20° C. to the reflux temperature of the solvent used. The reaction timemay vary depending upon the solvent used, the reaction temperature andthe like. In general, however, the reaction time is 10 min to 24 hr.

The compound of formula (18) thus obtained may be subjected toconventional post treatment. Further, isolation and purification may becarried out by optionally applying conventional methods such asprecipitation, crystallization, gel filtration, and columnchromatography on silica gel.

(Step II-2)

Step II-2 is the step of reacting the formyl group in the compound offormula (18) with a 3-metallopyridine of formula (19). Here a compoundof formula (4a) may be produced by reacting the compound of formula (18)with a separately prepared 3-metallopyridine in a solvent inert to thereaction.

The solvent used in step II-2 is not particularly limited and may beproperly selected by a person having ordinary skill in the art, so faras the solvent is inert to the reaction. Specific examples of solventsinclude ether, tetrahydrofuran, dioxane, toluene, and hexane. Thesolvent is preferably tetrahydrofuran.

The 3-metallopyridine may be prepared by a method well known to a personhaving ordinary skill in the art. For example, the 3-metallopyridine maybe prepared by reacting 3-bromopyridine, 3-iodopyridine or the like withan organolithium compound, such as n-butyllithium or t-butyllithium, ora Grignard reagent such as ethylmagnesium bromide or methylmagnesiumiodide, and metallic magnesium or the like, in a solvent such as ether,tetrahydrofuran, dioxane, toluene, or hexane at a temperature in a rangeof −100° C. to the reflux temperature of the solvent used for 10 min to24 hr.

In step II-2, the amount of 3-metallopyridine used is preferably 1 to 2molar equivalents relative to the compound of formula (18).

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range of−100° C. to the reflux temperature of the solvent used. The reactiontime may vary depending upon the solvent used, the reaction temperatureand the like. In general, however, the reaction time is 10 min to 24 hr.

The compound of formula (4a) may be subjected to conventional posttreatment. Further, isolation and purification may be carried out byoptionally applying conventional methods such as precipitation,crystallization, gel filtration, and column chromatography on silicagel.

(Step II-3)

Step II-3 is the step of protecting hydroxyl in the compound of formula(4a) to give the compound of formula (4) wherein one of Z¹ and Z²represents a hydrogen atom and the other represents protected hydroxyl(compound of formula (4′)).

The protective group of hydroxyl usable in step II-3 is not particularlylimited, and examples thereof include trialkylsilyl such ast-butyldimethylsilyl, trimethylsilyl, or triethylsilyl; oxycarbonyl suchas 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, orallyloxycarbonyl; and aralkyl such as benzyl and 4-methoxybenzyl. Theprotective group is preferably triethylsilyl.

This reaction for protecting hydroxyl may vary depending upon the typeof the protective group. However, this reaction may be carried out byusing as reference a reaction for protecting hydroxyl in a conventionalorganic synthetic reaction. For example, when the protective group istriethylsilyl, the compound of formula (4′) may be produced by reactingthe compound of formula (4a) using a triethylsilylating agent (forexample, triethylsilylchloride, or triethylsilyltrifluoromethanesulfonate) in an amount of 1 to 10 molar equivalentsrelative to the compound of formula (4a) in a solvent inert to thereaction (for example, methylene chloride, chloroform, tetrahydrofuran,or dimethylformamide) at a temperature in a range of −20° C. to thereflux temperature of the solvent used in the presence of a base (forexample, triethylamine, diisopropylethylamine, or imidazole) for 10 minto 24 hr.

The compound of formula (4′), (compound of formula (4) in which one ofZ¹ and Z² represents a hydrogen atom and the other represents protectedhydroxyl) thus obtained may be subjected to conventional post treatment.Further, isolation and purification may be carried out by optionallyapplying conventional methods such as precipitation, crystallization,gel filtration, and column chromatography on silica gel.

(Step II-4)

Step II-4 is a reaction for oxidizing hydroxyl in the compound offormula (4a) to give a compound of formula (4b) (compound of formula (4)wherein Z¹ and Z² together represent an oxygen atom).

In step II-4, the oxidation reaction of hydroxyl may be any oxidationreaction and may be properly carried out by a person having ordinaryskill in the art by using as reference the oxidation reaction ofhydroxyl in the conventional organic synthetic chemistry, so far as thereaction is inert to the atoms, other than hydroxyl, and any functionalgroup. For example, when the oxidation reaction is carried out usingmanganese dioxide, the compound of formula (4b) may be produced byreacting the compound of formula (4a) with manganese dioxide in anamount of 1 to 10 times by weight that of the compound of formula (4a)in a solvent inert to the reaction (for example, methylene chloride,chloroform, methanol, ethanol, ethyl acetate, or tetrahydrofuran) at atemperature in a range of −20° C. to the reflux temperature of thesolvent used for 10 min to 24 hr.

The compound of formula (4b) thus obtained may be subjected toconventional post treatment. Further, isolation and purification may becarried out by optionally applying conventional methods such asprecipitation, crystallization, gel filtration, and columnchromatography on silica gel.

(Step II-5)

Step II-5 is the step of protecting carbonyl in the compound of formula(4b) to give the compound of formula (4) wherein Z¹ and Z² togetherrepresent a protective group of carbonyl (compound of formula (4′)).

The protective group of carbonyl usable in step II-5 is not particularlylimited, and examples thereof include dialkoxy such as dimethoxy ordiethoxy; alkylenedioxy such as ethylenedioxy or trimethylenedioxy;alkylenedithio such as ethylenedithio or trimethylenedithio; hydrazonesuch as dimethylhydrazone or phenylhydrazone; and oxime, O-methyloxime,O-benzyloxime, or methylene. The protective group of carbonyl ispreferably dialkoxy such as dimethoxy or diethoxy; or hydrazone such asdimethylhydrazone, more preferably dimethoxy.

This reaction for protecting carbonyl may vary depending upon the typeof the protective group. The reaction, however, may be carried out byusing as reference a reaction for protecting carbonyl in theconventional organic synthetic reaction. For example, when theprotective group of carbonyl is dimethoxy, the compound of formula (4′)may be produced by treating the compound of formula (4b) with an acidsuch as sulfuric acid or tosylic acid in an amount of 1 to 30 molarequivalents relative to the compound of formula (4b) in the presence oftrimethyl orthoformate in an amount of 1 to 100 molar equivalentsrelative to the compound of formula (4b) in methanol at a temperature ina range of −20° C. to the reflux temperature for 10 min to 24 hr.

The compound of formula (4′) (compound of formula (4) wherein Z¹ and Z²together represent a protective group of carbonyl) may be subjected toconventional post treatment. Further, isolation and purification may becarried out by optionally applying conventional methods such asprecipitation, crystallization, gel filtration, and columnchromatography on silica gel.

The compound of formula (4), wherein Z¹ and Z² together represent anoxygen atom or a protective group of carbonyl, or alternatively one ofZ¹ and Z² represents a hydrogen atom with the other representinghydroxyl or protected hydroxyl and X represents a halogen atom, may beproperly produced by utilizing steps II-1 to II-5.

(Steps II-6 and II-7)

Step II-6 is the step of treating the compound of formula (4′) with aGrignard reagent in a solvent inert to the reaction. Step II-7 is thestep of reacting the compound prepared in step II-6 with a propionicacid derivative to give a compound of formula (6′).

The solvent used in step II-6 is not particularly limited and may beproperly selected by a person having ordinary skill in the art, so faras the solvent is inert to the reaction. Specific examples of solventsusable herein include methylene chloride, ether, tetrahydrofuran,dioxane, benzene, and toluene. The solvent is preferablytetrahydrofuran.

The Grignard reagent used is not particularly limited and may beproperly selected by a person having ordinary skill in the art. Specificexamples of the Grignard reagent include alkylmagnesium chlorides,alkylmagnesium bromides, alkylmagnesium iodides, and arylmagnesiumbromides. The Grignard reagent is preferably an alkylmagnesium bromide.The amount of the Grignard reagent used is preferably 1 to 2 molarequivalents relative to the compound of formula (4′).

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range of−100° C. to the reflux temperature of the solvent used. The reactiontime may vary depending upon the solvent used, the reaction temperatureand the like. In general, however, the reaction time is 10 min to 24 hr.

The reaction mixture as such may be used in step II-7.

The propionic acid derivative usable in step II-7 is, for example,selected from the group consisting of N-methyl-N-methoxypropionamide,propionic acid anhydride, propionyl chloride, and propionic acid(pyridin-2-ylthio)ester. The propionic acid derivative is preferablyN-methyl-N-methoxypropionamide. The amount of the propionic acidderivative used is preferably 1 to 3 molar equivalents relative to thecompound of formula (4′).

In one preferred embodiment of the present invention, the Grignardreagent is selected from the group consisting of alkylmagnesiumchlorides, alkylmagnesium bromides, alkylmagnesium iodides, andarylmagnesium bromides, and the propionic acid derivative is selectedfrom the group consisting of N-methyl-N-methoxypropionamide, propionicanhydride, propionyl chloride, and propionic acid(pyridin-2-ylthio)ester.

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range of−100° C. to the reflux temperature of the solvent used. The reactiontime may vary depending upon the solvent used, the reaction temperatureand the like. In general, however, the reaction time is 10 min to 24 hr.

The compound of formula (6′) may be subjected to conventional posttreatment. Further, isolation and purification may be carried out byoptionally applying conventional methods such as precipitation,crystallization, gel filtration, and column chromatography on silicagel.

The compound of formula (6), wherein Z¹ and Z² together represent anoxygen atom or a protective group of carbonyl, or alternatively one ofZ¹ and Z² represents a hydrogen atom and the other represents hydroxylor protected hydroxyl, may be properly produced by utilizing steps II-6and II-7 and conventional methods.

(III) Production of Compounds of Formula (1) wherein Y Represents anOxygen Atom

Compounds of formula (1) wherein Y represents an oxygen atom can besynthesized, for example, by the process shown in scheme III below.

wherein R¹, R¹¹, Z¹, Z², Z¹¹, Z¹², R⁷, and L¹ are as defined above.

In the present invention, the compound of formula (1) may be produced bysteps (f) and (g) below as shown in scheme III:

(f) the step of reacting a compound, prepared by treating the compoundof formula (6′) with an alkali metal base, or a base and a metal(I) to(IV) compound, with a compound of formula (7), optionally removing aprotective group and/or introducing a protective group and/or conductingoxidization, to give a compound of formula (8); and

(g) the step of reacting the compound of formula (8) with a compound offormula (9) in the presence of a base:

L²COCOOR²  (9)

wherein R² represents a protective group of carboxyl; and L² representsa leaving group.

Specifically, according to the process shown in scheme III, in stepIII-1, the compound of formula (6′) is converted to a metal enolate bytreating the compound of formula (6′) in a solvent inert to the reactionoptionally in the presence of an additive with an alkali metal base or abase and a metal(I) to (IV) compound. Subsequently, in step III-2, thecompound of formula (8) is produced by reacting this compound with thecompound of formula (7). If necessary, in step III-3, the step ofremoving the protective group and/or the step of conducting oxidizationand/or the step of introducing the protective group are carried out.Thereafter, in step III-4, the compound of formula (1) wherein Yrepresents an oxygen atom is produced by reacting the compound offormula (8) or formula (8′) with the compound of formula (9).

(Step III-1)

In step III-1, a method in which the compound of formula (6′) is treatedwith an alkali metal base to give a corresponding metal enolate(hereinafter often referred to as “method A”), or a method in which thecompound of formula (6′) is treated with a base and a metal (I) to (IV)compound to give a corresponding metal enolate (hereinafter oftenreferred to as “method B”).

Method A: The solvent used in method A is not particularly limited andmay be properly selected by a person having ordinary skill in the art,so far as the solvent is inert to the reaction. Specific examples ofsolvents include ether, tetrahydrofuran, dioxane, dimethoxyethane,toluene, and hexane. The solvent is preferably tetrahydrofuran.

Preferred additives usable herein include lithium salts such as lithiumchloride, lithium bromide, and lithium acetate. The amount of theadditive used is preferably 1 to 10 molar equivalents relative to thecompound of formula (6′).

The alkali metal base used may be any alkali metal base so far as it isa base having an alkali metal and has basicity high enough to abstract ahydrogen atom from α-position of carbonyl in the compound of formula(6′) to form the enolate. Specific examples of alkali metal basesinclude alkali metal amides such as lithium diisopropylamide, lithiumisopropylcyclohexylamide, lithium dicyclohexylamide, lithiumbistrimethylsilylamide, sodium bistrimethylsilylamide, potassiumbistrimethylsilylamide, bromomagnesium diisopropylamide, iodomagnesiumdiisopropylamide, bromomagnesium bistrimethylsilylamide, iodomagnesiumbistrimethylsilylamide, lithium-N-isopropyl-N-phenylamide, andlithium-N-isopropyl-N-naphthylamide; alkali metal hydrides such assodium hydride and potassium hydride; alkali metal alkoxides such aspotassium-t-butoxide and sodium-t-butoxide; and organolithium compoundssuch as n-butyllithium, methyllithium and phenyllithium. They may beused in combination of two or more. The alkali metal base is preferablylithium bistrimethylsilylamide. The amount of the alkali metal base usedis preferably 1 to 3 molar equivalents relative to the compound offormula (6′).

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range of−100° C. to the reflux temperature of the solvent used. The reactiontime may vary depending upon the solvent used, the reaction temperatureand the like. In general, however, the reaction time is 10 min to 24 hr.

Method B: The solvent used in method B is not particularly limited andmay be properly selected by a person having ordinary skill in the art,so far as the solvent is inert to the reaction. Specific examples ofsolvents include ether, tetrahydrofuran, dioxane, dimethoxyethane,toluene, hexane, methylene chloride, acetonitrile, anddimethylformamide. The solvent is preferably methylene chloride.

Bases usable herein include, for example, inorganic bases such as sodiumcarbonate, potassium carbonate, calcium carbonate, and sodiumhydrogencarbonate; tertiary amines such as triethylamine,diisopropylethylamine, tri-n-butylamine, N-ethylpiperidine, andN-methylmorpholine; aromatic amines such as pyridine, 2,6-lutidine, andN,N-dimethylaminopyridine; alkali metal amides such as lithiumdiisopropylamide, lithium isopropylcyclohexylamide, lithiumdicyclohexylamide, lithium bistrimethylsilylamide, sodiumbistrimethylsilylamide, potassium bistrimethylsilylamide, bromomagnesiumdiisopropylamide, iodomagnesium diisopropylamide, bromomagnesiumbistrimethylsilylamide, iodomagnesium bistrimethylsilylamide,lithium-N-isopropyl-N-phenylamide, andlithium-N-isopropyl-N-naphthylamide; and alkali metal alkoxides such aspotassium-t-butoxide and sodium-t-butoxide. The base is preferablytriethylamine, N-ethylpiperidine, pyridine, or 2,6-lutidine. The amountof the base used is preferably 1 to 5 molar equivalents relative to thecompound of formula (6′).

Metal(I) to (IV) compounds usable herein include, for example, titaniumtetrachloride, trichloroisopropoxy titanium, dichlorodiisopropoxytitanium, chlorotriisopropoxy titanium, titanium tetraisopropoxide,dichlorodicyclopentadienyl titanium, zirconium tetrachloride,dichlorodicyclopentadienyl zirconium, tin(II) trifluoromethanesulfonate,silver trifluoromethanesulfonate, copper(II) trifluoromethanesulfonate,zinc(II) trifluoromethanesulfonate, zinc chloride, zinc bromide, zinciodide, magnesium chloride, magnesium bromide, tin(II) chloride,chlorotrimethylsilane, trimethylsilyl trifluoromethanesulfonate,tert-butyldimethylsilyl trifluoromethanesulfonate, di-n-butylborontrifluoromethanesulfonate, boron trichloride, boron triisopropoxide, andethylene chloroboronate. The metal (I) to (IV) compound is preferablytin (II) trifluoromethanesulfonate. The amount of the metal (I) to (IV)compound used is preferably 1 to 5 molar equivalents relative to thecompound of formula (6′).

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range of−100° C. to the reflux temperature of the solvent used. The reactiontime may vary depending upon the solvent used, the reaction temperatureand the like. In general, however, the reaction time is 10 min to 24 hr.

The reaction mixture thus obtained as such may be used in step III-2.

(Step III-2)

Step III-2 is the step of reacting the reaction mixture prepared in stepIII-1 with the compound of formula (7) to give the compound of formula(8).

The compound of formula (7) used is a compound well known to a personhaving ordinary skill in the art and may be a commercially availablecompound, or alternatively may be properly synthesized by a conventionalmethod known to a person having ordinary skill in the art. The compoundof formula (7) is preferably(3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one(a compound of formula (20) below) because this compound is produced ona commercial scale, and, thus, a large amount thereof is available.

wherein Ac represents acetyl.

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range of−100° C. to the reflux temperature of the solvent used. The reactiontime may vary depending upon the solvent used, the reaction temperatureand the like. In general, however, the reaction time is 10 min to 24 hr.

The compound of formula (8) thus obtained may be subjected toconventional post treatment. Further, isolation and purification may becarried out by optionally applying conventional methods such asprecipitation, crystallization, gel filtration, and columnchromatography on silica gel.

(Step III-3)

Step III-3 may be an optional step. The compound of formula (8) preparedin step III-2 may be if necessary subjected to the step of removing aprotective group and/or the step of introducing a protective groupand/or the step of conducting oxidation.

For example, when Z¹ and Z² in formula (8) together represent theprotective group of carbonyl, this compound can be converted to thecompound of formula (8′) wherein Z¹¹ and Z¹² together represent anoxygen atom by removing the protective group in the compound of formula(8). The reaction for removing the protective group may vary dependingupon the type of the protective group. The reaction, however, may becarried out by using as reference a reaction for removing a protectivegroup of carbonyl in the conventional organic synthetic chemistry. Forexample, when Z¹ and Z² represent methoxy, dimethoxy as the protectivegroup may be removed by reacting the compound of formula (8) with anacid, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, ortrifluoroacetic acid, in an amount of 0.1 to 100 molar equivalentsrelative to the compound of formula (8), in a solvent inert to thereaction, for example, methanol, ethanol, water, tetrahydrofuran,dioxane, dimethylformamide, methylene chloride, chloroform, acetone, oracetonitrile, at a temperature in a range of −20° C. to the refluxtemperature of the solvent used for 10 min to 24 hr. In this case, theprotective group of hydroxyl in R¹ may be simultaneously removed tobring R¹ to a hydrogen atom.

When one of Z¹ and Z² in formula (8) represents a hydrogen atom with theother representing protected hydroxyl, this compound can be converted toa compound of formula (8′), wherein one of Z¹¹ and Z¹² represents ahydrogen atom with the other representing hydroxyl, by removing theprotective group of hydroxyl. The reaction for removing the protectivegroup of hydroxyl may vary depending upon the type of the protectivegroup. However, the reaction may be carried out by using as reference areaction for removing a protective group of hydroxyl in the conventionalorganic synthetic chemistry. For example, when the protective group ofhydroxyl is triethylsilyl, triethylsilyl as the protective group may beremoved by reacting the compound of formula (8) using an acid, such ashydrochloric acid, sulfuric acid, methanesulfonic acid, ortrifluoroacetic acid, or a fluorine reagent such as tetrabutylammoniumfluoride, in an amount of 0.1 to 100 molar equivalents relative to thecompound of formula (8) in a solvent inert to the reaction, for example,methanol, ethanol, water, tetrahydrofuran, dioxane, dimethylformamide,methylene chloride, chloroform, acetone, or acetonitrile, at atemperature in a range of −20° C. to the reflux temperature of thesolvent used for 10 min to 24 hr. Here the protective group of hydroxylin R¹ may be simultaneously removed to bring R¹ to a hydrogen atom.

When Z¹ and Z² in formula (8) are not such that they together representan oxygen atom, this compound can be converted to the compound offormula (8′), wherein Z¹¹ and Z¹² together represent an oxygen atom, byoxidizing the compound of formula (8). The oxidization reaction may becarried out by using as reference an oxidization reaction in theconventional organic synthetic chemistry. For example, when manganesedioxide is utilized in the oxidization reaction, the compound of formula(8′), wherein Z¹¹ and Z¹² together represent carbonyl, can be producedby reacting the compound of formula (8) with manganese dioxide in anamount of 1 to 10 times by weight that of the compound of formula (8),in a solvent inert to the reaction, for example, methylene chloride,chloroform, methanol, ethanol, ethyl acetate, or tetrahydrofuran, at atemperature in a range of −20° C. to the reflux temperature of thesolvent used for 10 min to 24 hr.

When R¹ in the compound of formula (8) represents a hydrogen atom, thehydroxyl group may be protected. Although the reaction for protectinghydroxyl may vary depending upon the type of the protective group, thereaction may be carried out by using as reference a reaction forprotecting hydroxyl in the conventional organic synthetic chemistry. Forexample, when the desired protective group is triethylsilyl, thecompound of formula (8′) wherein R¹ represents protected hydroxyl can beproduced by reacting the compound of formula (8), wherein R¹ representsa hydrogen atom, with a triethylsilylating agent, for example,triethylsilylchloride or triethylsilyl trifluoromethanesulfonate, in anamount of 1 to 10 molar equivalents relative to the compound of formula(8) in a solvent inert to the reaction, for example, methylene chloride,chloroform, tetrahydrofuran, or dimethylformamide, at a temperature in arange of −20° C. to the reflux temperature of the solvent used in thepresence of a base such as triethylamine, diisopropylethylamine, orimidazole for 10 min to 24 hr.

When R⁷ in the compound of formula (8) represents a protective group ofamino, this compound can be converted to the compound of formula (8),wherein R⁷ represents a hydrogen atom, by removing the protective group.The reaction for removing the protective group of amino may varydepending upon the type of the protective group. The reaction, however,may be carried out by using as reference a reaction for removing theprotective group of amino in the conventional organic syntheticchemistry. For example, when the protective group of amino istriethylsilyl, the protective group may be removed by reacting thecompound of formula (8) with an acid such as hydrochloric acid, sulfuricacid, methanesulfonic acid, or trifluoroacetic acid, or a fluorinereagent such as tetrabutylammonium fluoride, in an amount of 0.1 to 100molar equivalents relative to the compound of formula (8) in a solventinert to the reaction, for example, methanol, ethanol, water,tetrahydrofuran, dioxane, dimethyl, formamide, methylene chloride,chloroform, acetone, or acetonitrile, at a temperature in a range of−20° C. to the reflux temperature of the solvent used for 10 min to 24hr.

The compound of formula (8′) wherein R¹ represents protected hydroxylthus obtained may be subjected to conventional post treatment. Further,isolation and purification may be carried out by optionally applyingconventional methods such as precipitation, crystallization, gelfiltration, and column chromatography on silica gel.

In Z¹ and Z² in formula (8), all forms included in this formula aremutually convertible by step III-3. Likewise, in the substituents of R¹and R⁷, all forms included in this formula are mutually convertible.Accordingly, if necessary, the compound of formula (8) may be convertedto the compound of formula (8′). Likewise, if necessary, the compound offormula (8′) may also be converted to the compound of formula (8).

(Step III-4)

Step III-4 is the step of reacting the compound of formula (8) orformula (8′) with the compound of formula (9) in the presence of a baseto give the compound of formula (1) wherein Y represents an oxygen atom.

The solvent used in step III-4 is not particularly limited and may beproperly synthesized by a person having ordinary skill in the art, sofar as the solvent is inert to this reaction. Specific examples ofsolvents include methylene chloride, chloroform, ether, tetrahydrofuran,toluene, acetonitrile, and dimethylformamide. The solvent is preferablymethylene chloride, tetrahydrofuran, or toluene.

The compound of formula (9) may be a commercially available product, oralternatively is easily available by synthesis by a conventional methodknown to a person having ordinary skill in the art. The amount of thecompound of formula (9) used is preferably 1 to 3 molar equivalentsbased on the compound of formula (8).

Bases usable herein include, for example, inorganic bases, for example,sodium carbonate, potassium carbonate, calcium carbonate, and sodiumhydrogencarbonate; tertiary amines such as triethylamine,diisopropylethylamine, tri-n-butylamine, N-ethylpiperidine, andN-methylmorpholine; aromatic amines such as pyridine, 2,6-lutidine, andN,N-dimethylaminopyridine; and alkali metal amides such as lithiumdiisopropylamide, lithium isopropylcyclohexylamide, lithiumdicyclohexylamide, lithium bistrimethylsilylamide, sodiumbistrimethylsilylamide, potassium bistrimethylsilylamide, bromomagnesiumdiisopropylamide, iodomagnesium diisopropylamide, bromomagnesiumbistrimethylsilylamide, iodomagnesium bistrimethylsilylamide,lithium-N-isopropyl-N-phenylamide, andlithium-N-isopropyl-N-naphthylamide. The base is preferablytriethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine. Theamount of the base used is preferably 1 to 3 molar equivalents relativeto the compound of formula (8) or formula (8′).

The reaction temperature may vary depending upon the solvent used andthe like. In general, however, the reaction temperature is in a range of−80° C. to the reflux temperature of the solvent used. The reaction timemay vary depending upon the solvent used, the reaction temperature andthe like. In general, however, the reaction time is 10 min to 24 hr.

The compound of formula (1) wherein Y═O thus obtained may be subjectedto conventional post treatment. Further, isolation and purification maybe carried out by optionally applying conventional methods such asprecipitation, crystallization, gel filtration, and columnchromatography on silica gel.

(IV) Production of Compounds of Formula (1) wherein Y Represents GroupP(R³)³ (a)

Compounds of formula (1), wherein Y represents group P(R³)³, can besynthesized, for example, by the process shown in scheme IV below.

wherein R¹, R¹¹, R², R³, Z¹, Z², Z¹¹, and Z¹² are as defined above; andX^(a) represents a halogen atom.

In the present invention, as shown in scheme IV, the production processof the compound of formula (1) wherein Y represents group P(R³)₃comprises reacting the compound of formula (8) (preferably a compound offormula (8′)) with a compound of formula (10) or its reactive equivalentto give a compound of formula (11), halogenating hydroxyl in thecompound of formula (11) with a halogenating agent, and reacting theresultant compound (typically a compound of formula (12)) with acompound of formula (13). The compound of formula (10) and the compoundof formula (13) are as follows:

HC(═O)—COOR²  (10)

P(R³)₃  (13)

wherein R² and R³ are as defined above.

The “reactive equivalent” of the compound of formula (10) as used hereinmay be any compound that is a compound which can cause a reactionequivalent to the reaction caused when the compound of formula (10) isused and can be easily selected by a person having ordinary skill in theart. Specific examples of the “reactive equivalent” include hydrates ofthe compound of formula (10) and hemiacetals thereof. For example,monohydrate (HOCH(OH)COOR²) may be mentioned as a suitable hydrate ofthe compound of formula (10). The “reactive equivalent” of the compoundof formula (10) is preferably monohydrate, more preferably glyoxylicacid (4-nitrobenzyl)ester monohydrate or glyoxylic acid allyl estermonohydrate.

Specifically, according to the process shown in scheme IV, in step IV-1,the compound of formula (11) is produced by reacting the compound offormula (8′) with the compound of formula (10) or its reactiveequivalent. In step IV-2, the compound of formula (12) is produced byreacting hydroxyl in the compound of formula (11) with a halogenatingagent in the presence of a base. In step IV-3, the compound of formula(1) is produced by reacting the compound of formula (12) with thecompound of formula (13).

(Step IV-1)

The solvent used in step IV-1 is not particularly limited and may beproperly synthesized by a person having ordinary skill in the art, sofar as the solvent is inert to the reaction. Specific examples ofsolvents include benzene, toluene, xylene, dioxane, anddimethylformamide. The solvent is preferably toluene.

The compound of formula (10) or its reactive equivalent may be acommercially available product, or alternatively is easily available bysynthesis by a conventional method known to a person having ordinaryskill in the art. The amount of the compound of formula (10) or itsreactive equivalent used is preferably 1 to 3 molar equivalents relativeto the compound of formula (8′).

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range ofroom temperature to the reflux temperature of the solvent used. Thereaction time may vary depending upon the solvent used, the reactiontemperature and the like. In general, however, the reaction time is 10min to 24 hr.

The compound of formula (11) thus obtained may be subjected toconventional post treatment. Further, isolation and purification may becarried out by optionally applying conventional methods such asprecipitation, crystallization, gel filtration, and columnchromatography on silica gel.

(Step IV-2)

The solvent used in step IV-2 is not particularly limited and may beproperly synthesized by a person having ordinary skill in the art, sofar as the solvent is inert to the reaction. Specific examples ofsolvents include ether, tetrahydrofuran, dioxane, methylene chloride,chloroform, ethyl acetate, toluene, and dimethylformamide. The solventis preferably tetrahydrofuran.

The halogenating agent may be any conventional halogenating agent.Specific examples of halogenating agents include thionyl chloride,thionyl bromide, phosphorusoxy chloride, and phosphorusoxy bromide.Preferably, the halogenating agent is thionyl chloride. The amount ofthe halogenating agent used is preferably 1 to 3 equivalents relative tothe compound of formula (11).

Bases usable herein include, for example, tertiary amines such astriethylamine, diisopropylethylamine, tri-n-butylamine,N-ethylpiperidine, and N-methylmorpholine; and aromatic amines such aspyridine, 2,6-lutidine, and N,N-dimethylaminopyridine. The base ispreferably pyridine or 2,6-lutidine. The amount of the base used ispreferably 1 to 3 molar equivalents relative to the compound of formula(11).

The reaction temperature may vary depending upon the solvent used andthe like. In general, however, the reaction temperature is in a range of−50° C. to the reflux temperature of the solvent used. The reaction timemay vary depending upon the solvent used, the reaction temperature andthe like. In general, however, the reaction time is 10 min to 24 hr.

The compound of formula (12) may be subjected to conventional posttreatment. Further, isolation and purification may be carried out byoptionally applying conventional methods such as precipitation,crystallization, gel filtration, and column chromatography on silicagel.

(Step IV-3)

The solvent used in step IV-3 is not particularly limited and may beproperly synthesized by a person having ordinary skill in the art, sofar as the solvent is inert to the reaction. Specific examples ofsolvents include hexane, toluene, ether, tetrahydrofuran, dioxane, anddimethylformamide. The solvent is preferably dimethylformamide.

Examples of the compound of formula (13) include tri-n-butylphosphine,tri-t-butylphosphine, triphenylphosphine, and tri-p-tolylphosphine. Thecompound of formula (13) is preferably triphenylphosphine. The compoundof formula (13) may be a commercially available product, oralternatively is easily available by synthesis by a conventional methodknown to a person having ordinary skill in the art. The amount of thecompound of formula (13) used is preferably 1 to 3 molar equivalentsrelative to the compound of formula (12).

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range ofroom temperature to the reflux temperature of the solvent used. Thereaction time may vary depending upon the solvent used, the reactiontemperature and the like. In general, however, the reaction time is 10min to 24 hr.

The compound of formula (1), wherein Y represents group P(R³)₃, may besubjected to conventional post treatment. Further, isolation andpurification may be carried out by optionally applying conventionalmethods such as precipitation, crystallization, gel filtration, andcolumn chromatography on silica gel.

(V) Production of Compounds of Formula (1) wherein Y Represents GroupP(R³)³ (b)

Compounds of formula (1) wherein Y represents group P(R³)³ can also besynthesized, for example, by the process shown in scheme V below.

wherein R¹, R¹¹, R², R³, R⁴, Z¹, Z², Z¹¹, Z¹², and X are as definedabove.

In the present invention, as shown in scheme V, the production processof the compound of formula (1) wherein Y represents group P(R³)₃comprises reacting the reaction mixture, prepared by treating thecompound of formula (4′) with a Grignard reagent, with the compound offormula (5).

Specifically, according to the process shown in scheme V, in a solventinert to the reaction, in step V-1, the compound of formula (4)(preferably the compound of formula (4′)) is treated with a Grignardreagent, and, subsequently, in step V-2, the compound of formula (1),wherein Y represents group P(R³)₃, is produced by reacting the reactionmixture with the compound of formula (5).

(Step V-1)

The solvent used in step V-1 is not particularly limited and may beproperly synthesized by a person having ordinary skill in the art, sofar as the solvent is inert to the reaction. Specific examples ofsolvents include methylene chloride, ether, tetrahydrofuran, dioxane,benzene, and toluene. Preferably, the solvent is tetrahydrofuran.

Grignard reagents include, for example, alkylmagnesium chlorides,alkylmagnesium bromides, alkylmagnesium iodides, and arylmagnesiumbromides. The Grignard reagent is preferably an alkylmagnesium bromide.The amount of Grignard reagent used is preferably 1 to 2 molarequivalents relative to the compound of formula (4′).

In one preferred embodiment of the present invention, the treatment withthe Grignard reagent is carried out using an alkylmagnesium bromide asthe Grignard reagent in a solvent selected from the group consisting ofmethylene chloride, ether, tetrahydrofuran, dioxane, benzene, andtoluene.

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range of−100° C. to the reflux temperature of the solvent used. The reactiontime may vary depending upon the solvent used, the reaction temperatureand the like. In general, however, the reaction time is 10 min to 24 hr.

The reaction mixture thus obtained as such may be used in step V-2.

(Step V-2)

The solvent used in step V-2 is not particularly limited and may beproperly synthesized by a person having ordinary skill in the art, sofar as the solvent is inert to the reaction. Specific examples ofsolvents include methylene chloride, ether, tetrahydrofuran, dioxane,benzene, and toluene. The solvent is preferably toluene ortetrahydrofuran.

The compound of formula (5) is available by synthesis by the methoddescribed in WO01/53305. Examples of preferred compounds of formula (5)include(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-(4-dimethylaminobenzoyloxycarbonyl)ethyl]azetidin-2-one,or (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-(4-diethylaminobenzoyloxycarbonyl)ethyl]azetidin-2-one.The amount of the compound of formula (5) used is preferably 1 to 3molar equivalents relative to the compound of formula (4′).

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range of−100° C. to the reflux temperature of the solvent used. The reactiontime may vary depending upon the solvent used, the reaction temperatureand the like. In general, however, the reaction time is 10 min to 24 hr.

The compound of formula (1) wherein Y represents group P(R³)₃ thusobtained may be subjected to conventional post treatment. Further,isolation and purification may be carried out by optionally applyingconventional methods such as precipitation, crystallization, gelfiltration, and column chromatography on silica gel.

When Z¹ and Z² in formula (1) together represent the protective group ofcarbonyl, this compound can be converted to the compound of formula (1)wherein Z¹ and Z² together represent an oxygen atom by removing theprotective group. The reaction for removing the protective group mayvary depending upon the type of the protective group. The reaction,however, may be carried out by using as reference a reaction forremoving a protective group of carbonyl in the conventional organicsynthetic chemistry. For example, when Z¹ and Z² represent methoxy,dimethoxy as the protective group may be removed by reacting thecompound of formula (1) with an acid, such as hydrochloric acid,sulfuric acid, methanesulfonic acid, or trifluoroacetic acid, in anamount of 0.1 to 100 molar equivalents relative to the compound offormula (1), in a solvent inert to the reaction, for example, methanol,ethanol, water, tetrahydrofuran, dioxane, dimethylformamide, methylenechloride, chloroform, acetone, or acetonitrile, at a temperature in arange of −20° C. to the reflux temperature of the solvent used for 10min to 24 hr. In this case, the protective group of hydroxyl in R¹ maybe simultaneously removed to bring R¹ to a hydrogen atom.

When one of Z¹ and Z² in formula (1) represents a hydrogen atom with theother representing protected hydroxyl, this compound can be converted tothe compound of formula (1), wherein one of Z¹ and Z² represents ahydrogen atom with the other representing hydroxyl, by removing theprotective group of hydroxyl. Upon an additional oxidation reaction, thecompound can be converted to the compound of formula (1) wherein Z¹ andZ² together represent an oxygen atom. The reaction for removing theprotective group of hydroxyl may vary depending upon the type of theprotective group. However, the reaction may be carried out by using asreference a reaction for removing a protective group of hydroxyl in theconventional organic synthetic chemistry. For example, when theprotective group of hydroxyl is triethylsilyl, triethylsilyl as theprotective group may be removed by reacting the compound of formula (1)using an acid, such as hydrochloric acid, sulfuric acid, methanesulfonicacid, or trifluoroacetic acid, or a fluorine reagent such astetrabutylammonium fluoride, in an amount of 0.1 to 100 molarequivalents relative to the compound of formula (1) in a solvent inertto the reaction, for example, methanol, ethanol, water, tetrahydrofuran,dioxane, dimethylformamide, methylene chloride, chloroform, acetone, oracetonitrile, at a temperature in a range of −20° C. to the refluxtemperature of the solvent used for 10 min to 24 hr. Here the protectivegroup of hydroxyl in R¹ may be simultaneously removed to bring R¹ to ahydrogen atom. The oxidization reaction may be carried out by using asreference an oxidization reaction in the conventional organic syntheticchemistry. For example, when manganese dioxide is utilized in theoxidization reaction, the compound of formula (1), wherein Z¹ and Z²together represent carbonyl, can be produced by reacting the compound offormula (1) with manganese dioxide in an amount of 1 to 10 times byweight that of the compound of formula (1), in a solvent inert to thereaction, for example, methylene chloride, chloroform, methanol,ethanol, ethyl acetate, or tetrahydrofuran, at a temperature in a rangeof −20° C. to the reflux temperature of the solvent used for 10 min to24 hr.

The compound of formula (1) thus obtained may be subjected toconventional post treatment. Further, isolation and purification may becarried out by optionally applying conventional methods such asprecipitation, crystallization, gel filtration, and columnchromatography on silica gel.

The compound of formula (2) may be produced by treating the compound offormula (1) under conditions which can form a carbapenem ring.Conditions for carbapenem ring formation are well known to a personhaving ordinary skill in the art.

(VI) Production of Compounds of Formula (2) (a)

Compounds of formula (2) can be synthesized from the compound of formula(1) wherein Y represents oxygen by the process shown below.

wherein R¹, R², R, Z¹, and Z² are as defined above.

In the present invention, the production process of the compound offormula (2) comprises treating the compound of formula (1) underconditions for carbapenem ring formation to form a carbapenem ringthrough a ring-closing reaction and optionally subjecting the resultantcompound to the removal of the protective group and/or oxidation.

According to the process shown in scheme VI, the compound of formula (2)is produced by reacting the compound of formula (1), wherein Yrepresents an oxygen atom, with the compound of formula (21) in asolvent inert to the reaction.

P(R⁹)₃  (21)

wherein R⁹s, which may be the same or different, represent C1-6 alkyl orC1-6 alkoxy.

Accordingly, in one preferred embodiment of the present invention, thetreatment for carbapenem ring formation is carried out by reacting thecompound of formula (1) with the compound of formula (21).

The solvent used is not particularly limited and may be properlysynthesized by a person having ordinary skill in the art, so far as thesolvent is inert to the reaction. Specific examples of solvents includehexane, methylene chloride, chloroform, isopropyl alcohol, ether,tetrahydrofuran, dioxane, and toluene. The solvent is preferablyisopropyl alcohol or toluene.

Compounds of formula (21) include, for example, triethyl phosphite,trimethyl phosphite and dimethyl methylphosphonite, and diethylmethylphosphonite. The compound of formula (21) is preferably diethylmethylphosphonite. The compound of formula (21) may be a commerciallyavailable product, or alternatively is easily available by synthesis bya conventional method known to a person having ordinary skill in theart. The amount of the compound of formula (21) used is preferably 1 to10 molar equivalents relative to the compound of formula (1).

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range ofroom temperature to the reflux temperature of the solvent used. Thereaction time may vary depending upon the solvent used, the reactiontemperature and the like. In general, however, the reaction time is 10min to 24 hr.

The compound of formula (2) thus obtained may be subjected toconventional post treatment. Further, isolation and purification may becarried out by optionally applying conventional methods such asprecipitation, crystallization, gel filtration, and columnchromatography on silica gel.

(VII) Production of Compounds of Formula (2) (b)

The compound of formula (2) can be synthesized from the compound offormula (1) wherein Y represents group P(R³)₃ by the process shown inscheme VII below.

wherein R¹, R², R³, R, Z¹, and Z² are as defined above.

In the present invention, the production process of the compound offormula (2) comprises treating the compound of formula (1) underconditions for carbapenem ring formation to form a carbapenem ringthrough a ring-closing reaction and optionally subjecting the resultantcompound to the removal of the protective group and/or oxidation.

According to the process shown in scheme VII, the compound of formula(2) is produced by eliminating group O═P(R³)₃ from the compound offormula (1) wherein Y represents P(R³)₃, to form a ring.

Accordingly, in one preferred embodiment of the present invention, thetreatment for carbapenem ring formation is carried out by eliminatinggroup O═P(R³)₃ from the compound of formula (1).

The solvent used is not particularly limited and may be properlysynthesized by a person having ordinary skill in the art, so far as thesolvent is inert to the reaction. Specific examples of solvents includehexane, methylene chloride, chloroform, isopropyl alcohol, ether,tetrahydrofuran, dioxane, and toluene. The solvent is preferablytoluene. The amount of the solvent used is preferably about 5 to 100times by weight of that of the compound of formula (1).

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range ofroom temperature to the reflux temperature of the solvent used. Thereaction time may vary depending upon the solvent used, the reactiontemperature and the like. In general, however, the reaction time is 10min to 24 hr.

When Z¹ and Z² in formula (2) together represent the protective group ofcarbonyl, this compound can be converted to the compound of formula (2)wherein Z¹ and Z² together represent an oxygen atom by removing theprotective group. The reaction for removing the protective group mayvary depending upon the type of the protective group. The reaction,however, may be carried out by using as reference a reaction forremoving a protective group of carbonyl in the conventional organicsynthetic chemistry. In this case, the protective group of hydroxyl inR¹ may be simultaneously removed to bring R¹ to a hydrogen atom.

When one of Z¹ and Z² in formula (2) represents a hydrogen atom with theother representing protected hydroxyl, this compound can be converted tothe compound of formula (2), wherein one of Z¹ and Z² represents ahydrogen atom with the other representing hydroxyl, by removing theprotective group of hydroxyl. Upon an additional oxidation reaction, thecompound can be converted to the compound of formula (2) wherein Z¹ andZ² together represent an oxygen atom. The reaction for removing theprotective group of hydroxyl may vary depending upon the type of theprotective group. However, the reaction may be carried out by using asreference a reaction for removing a protective group of hydroxyl in theconventional organic synthetic chemistry. In this case, the protectivegroup of hydroxyl in R¹ may be simultaneously removed to bring R¹ to ahydrogen atom. The oxidization reaction may be carried out by using asreference an oxidization reaction in the conventional organic syntheticchemistry.

The compound of formula (2) thus obtained may be subjected toconventional post treatment. Further, isolation and purification may becarried out by optionally applying conventional methods such asprecipitation, crystallization, gel filtration, and columnchromatography on silica gel.

(VIII) Production of Compounds of Formula (3)

Compounds of formula (3) can be synthesized from the compound of formula(2) by the process shown in scheme VIII below.

wherein R¹, R, L³, Z¹, and Z² are as defined above.

In the present invention, the compound of formula (3) can be produced byreacting the compound of formula (2) with the compound of formula (iv).

L³CH₂CONH₂  (iv)

wherein L³ represents a leaving group.

The solvent used herein is not particularly limited and may be properlysynthesized by a person having ordinary skill in the art, so far as thesolvent is inert to the reaction. Specific examples of solvents includeacetone, methanol, ethanol, isopropanol, and dioxane. The solvent ispreferably methanol.

Examples of compounds of formula (iv) include bromoacetamide,iodoacetamide, and trifluoromethanesulfonyloxyacetamide. The compound offormula (iv) is preferably iodoacetamide.

The compound of formula (iv) may be a commercially available product, oralternatively is easily available by synthesis by a conventional methodknown to a person having ordinary skill in the art. The amount of thecompound of formula (iv) used is preferably 1 to 5 molar equivalentsrelative to the compound of formula (2).

The reaction temperature may vary depending upon the solvent used or thelike. In general, however, the reaction temperature is in a range of−20° C. to the reflux temperature of the solvent used. The reaction timemay vary depending upon the solvent used, the reaction temperature andthe like. In general, however, the reaction time is 10 min to 24 hr.

The compound of formula (3) thus obtained may be subjected toconventional post treatment. Further, isolation and purification may becarried out by optionally applying conventional methods such asprecipitation, crystallization, gel filtration, and columnchromatography on silica gel.

(IX) Production of Compounds of Formula (A)

Compounds of formula (A) can be synthesized from the compound of formula(2) by the process shown in scheme IX.

wherein R¹, R, and L³ are as defined above.

The compound of formula (A) can be produced by removing the protectivegroup of the compound of formula (3) by deprotection. The reaction forremoving the protective group of hydroxyl and the protective group ofcarboxyl may vary depending upon the type of the protective group. Thereaction, however, may be carried out by using as reference a reactionfor removing a protective group of hydroxyl in the conventional organicsynthetic chemistry. For example, when the protective group R¹ ofhydroxyl is triethylsilyl, triethylsilyl as the protective group can beremoved by reacting the compound of formula (3) with an acid such ashydrochloric acid, sulfuric acid, methanesulfonic acid, ortrifluoroacetic acid, or a fluorine reagent such as tetrabutylammoniumfluoride, in an amount of 0.1 to 10 molar equivalents relative to thecompound of formula (3) in a solvent inert to the reaction, for example,methanol, ethanol, water, tetrahydrofuran, dioxane, dimethylformamide,methylene chloride, chloroform, acetone, or acetonitrile, at atemperature in a range of −20° C. to the reflux temperature of thesolvent used for 10 min to 24 hr. When the protective group R ofcarboxyl is 4-nitrobenzyl (pNB), the protective group can be removed bythe method described in WO 02/42314.

In one preferred embodiment of the present invention, the compound offormula (A) is produced by removing the protective group of the compoundof formula (3) by deprotection.

The compound of formula (A) thus obtained may be subjected toconventional post treatment. Further, isolation and purification may becarried out by optionally applying conventional methods such asprecipitation, crystallization, gel filtration, and columnchromatography on silica gel.

In another embodiment of the present invention, the production processof the compound of formula (A) comprises preparing the compound offormula (2) from the compound of formula (1) by the production processof the compound of formula (2). Preferably, the production process ofthe compound of formula (A) further comprises preparing the compound offormula (1) by the production process of the compound of formula (1).

Use of Compounds

The compounds of formula (1), formula (4), formula (6), formula (8), andformula (14a) according to the present invention are useful asintermediates for the production of carbapenem derivatives (compound offormula (A)) having7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazole atthe 2-position on the carbapenem ring.

As disclosed in WO 02/42312, carbapenem derivatives of formula (A)produced by using compounds of formula (1) according to the presentinvention have high antimicrobial activities against a wide spectrum ofGram-positive bacteria and Gram-negative bacteria and, at the same time,have high antimicrobial activities against MRSA, PRSP, Haemophilusinfluenzae and β-lactamase producing bacteria. Further, as disclosed inthis publication, they have low toxicity and are also stable to DHP-1.Use of the above derivatives as therapeutic agents of infectiousdiseases caused by various pathogenic bacteria in animals includinghumans, and the manufacture of pharmaceutical compositions using theabove compounds will be apparent to a person having ordinary skill inthe art by reference to the above publication.

EXAMPLES

The present invention is further illustrated by the following Examplesthat are not intended as a limitation of the invention.

Example 1 5-Bromo-2-t-butoxycarbonylaminomethylthiazole

A solution (2 L) of 1.33 kg of 2-t-butoxy carbonylaminomethylthiazole inethyl acetate was added to an aqueous solution (20 L) of 8.6 kg ofsodium acetate, and the mixture was stirred. Bromine (1.35 L) was addeddropwise to this solution (internal temperature: 19 to 24° C.) over aperiod of 3.5 hr, and the mixture was stirred at an internal temperatureof 25.5±5° C. for 14 hr. Sodium sulfite pentahydrate (180 g) was addedthereto, the mixture was then extracted with 3 L of ethyl acetate, andthe organic layer was washed with 1 L of water and 1.53 L of a 6 Maqueous sodium hydroxide solution. The aqueous layer was then extractedwith 3 L of ethyl acetate. The organic layers were combined, were driedover anhydrous magnesium sulfate, and were filtered. The solvent wasremoved from the filtrate by evaporation under the reduced pressure,followed by substitution concentration twice with 2 L of ethanol to give944 g of 5-bromo-2-t-butoxy carbonylaminomethylthiazole.

¹H-NMR (CDCl₃) δ: 1.40 (9H, s), 4.48 (2H, d, J=6.1 Hz), 5.16 (1H, brs),7.51 (1H, s)

Example 2 2-Aminomethyl-5-bromothiazole hydrochloride

4 N hydrochloric acid dioxane solution (2.3 L) was added dropwise to asolution (1.6 L) of 542 g of5-bromo-2-t-butoxycarbonylaminomethylthiazole in ethanol at an internaltemperature of 40° C. over a period of 1.1 hr. The mixture was stirreduntil the internal temperature reached 23° C. The precipitated crystalwas collected by filtration, was washed twice with ethanol, and was thendried under the reduced pressure to give 394 g of2-aminomethyl-5-bromothiazole hydrochloride.

¹H-NMR (CDCl₃) δ: 4.37 (2H, s), 7.72 (1H, s)

Example 3 5-Bromo-2-formylaminomethylthiazole

2-Aminomethyl-5-bromothiazole hydrochloride (350 g) was dissolved in 7 Lof ethyl formate. To this solution were added 296 ml of a 28% methanolsolution of sodium methoxide and 173 ml of a formic acid solution. Themixture was then stirred at an internal temperature of 48° C. for 5 hr.The solvent was removed by evaporation under the reduced pressure. Whenprecipitate occurred, ethanol was added to dissolve the precipitate. Thesolvent was again removed by evaporation under the reduced pressureuntil crystal was formed. The solution was stirred under ice coolingovernight. The precipitated crystal was then collected by filtration,was then washed with cold ethanol and hexane, and was dried under thereduced pressure to give 189 g of 5-bromo-2-formylaminomethylthiazole.Further, the filtrate was concentrated, and the concentrate wascrystallized from ethanol to give 58 g of secondary crystal.

¹H-NMR (CDCl₃) δ: 4.71 (2H, d, J=6.6 Hz), 6.58 (1H, s), 7.59 (1H, s),8.29 (1H, s)

Example 4 5-Bromo-2-formylaminomethylthiazole

2-Formylaminomethylthiazole (200 g) was added to a solution of 4.5 kg ofsodium dihydrogenphosphate dihydrate in 6 L of water, and the mixturewas stirred at 30° C. Sodium bromide (4.0 kg) and 2 L of tetrahydrofuranwere added thereto in that order. Bromine (1.49 kg) was added whileadjusting the solution to pH 3 by the addition of a 6 N aqueous sodiumhydroxide solution, and the mixture was stirred for 2 hr. The reactionmixture was added to a solution of 500 g of sodium sulfite in 4 L ofwater to stop the reaction and was then adjusted to pH 4.9 by theaddition of a 6 N aqueous sodium hydroxide solution while maintainingthe temperature of the mixture at 30° C. The reaction mixture wasextracted with 10 L of ethyl acetate and then with 5 L of ethyl acetate.The organic layers were combined and were dried over anhydrous magnesiumsulfate. The solvent was removed to bring the volume to 1 L, and theconcentrate was stirred at 6° C. for 12 hr for crystallization to give104.4 g of 5-bromo-2-formylaminomethylthiazole. The results of NMRanalysis were in agreement with the results of analysis in Example 3.

Example 5 2-Bromoimidazo[5,1-b]thiazole

Toluene (1.0 L) was added to 104 g of5-bromo-2-formylaminomethylthiazole, and the mixture was heated to 90°C. and was stirred. A solution of 65.8 g of phosphorus oxychloride in100 ml of toluene was added to the reaction mixture, and the mixture wasstirred at that temperature for 1.5 hr. After standing to cool, 2 L of a0.5 N aqueous hydrochloric acid solution was added, and the aqueouslayer was separated. The aqueous layer was adjusted to pH 6.2 by theaddition of a 5 N aqueous sodium hydroxide solution and was extractedwith 1.5 L of ethyl acetate and then with 1.0 L of ethyl acetate. Theorganic layers were combined, were washed with a 5% aqueous sodiumbicarbonate solution and a 20% aqueous sodium chloride solution in thatorder, and were dried over anhydrous magnesium sulfate. The solvent wasremoved to bring the volume to about 100 ml, 500 ml of ethylacetate:hexane=1:4 solution was added thereto, and the mixture wasstirred in an ice-water bath for crystallization to give 57.6 g of2-bromimidazo[5,1-b]thiazole.

¹H-NMR (CDCl₃) δ: 7.05 (1H, s), 7.48 (1H, s), 7.96 (1H, s)

Example 6 2-Bromo-7-formylimidazo[5,1-b]thiazole

Dimethylformamide (0.13 ml) and 0.15 ml of phosphorus oxychloride wereadded in that order to a solution of 300 mg of2-bromoimidazo[5,1-b]thiazole in 3 ml of methylene chloride under anargon atmosphere, and the mixture was stirred at 80° C. for 6 hr. Waterwas added to the reaction mixture to stop the reaction, and the reactionmixture was adjusted to pH 10 by the addition of a 1 N aqueous sodiumhydroxide solution. The reaction mixture was then extracted with ethylacetate, and the organic layer was then washed with saturated brine andwas dried over magnesium sulfate. The solvent was removed byevaporation, and the residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=1:10) to give 223 mg of2-bromo-7-formylimidazo[5,1-b]thiazole.

¹H-NMR (CDCl₃) δ: 7.66 (1H, s), 8.02 (1H, s), 9.90 (1H, s)

Example 7 2-Bromo-7-hydroxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole

A 1 M tetrahydrofuran solution (0.9 ml) of ethylmagnesium bromide wasadded to a solution of 147 mg of 3-iodopyridine in 1 ml oftetrahydrofuran under an argon atmosphere, and the mixture was stirredat room temperature for 30 min. A solution of 149 mg of2-bromo-7-formylimidazo[5,1-b]thiazole in 2 ml of tetrahydrofuran wasadded to the solution, and the mixture was stirred at that temperaturefor 2.5 hr. An aqueous saturated ammonium chloride solution was added tothe reaction mixture to stop the reaction, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine in that order and was then dried over magnesiumsulfate. The solvent was removed by evaporation, and the residue waspurified by column chromatography on silica gel (ethylacetate:methanol=4:1) to give 147 mg of2-bromo-7-(pyridin-3-yl)hydroxymethylimidazo[5,1-b]thiazole.

¹H-NMR (CDCl₃) δ: 6.04 (1H, s), 7.32-7.36 (1H, m), 7.84 (1H, s), 7.91(1H, s), 8.58 (1H, dd, J=2.2, 4.7 Hz), 8.67 (1H, d, J=2.2 Hz)

Example 82-Bromo-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole

Diisopropylethylamine (3.1 ml) and 3.0 ml of triethylsilylchloride wereadded in that order to a solution of 4.05 g of2-bromo-7-(pyridin-3-yl)hydroxymethylimidazo[5,1-b]thiazole in 30 ml ofdimethylformamide, and the mixture was stirred at room temperature forone hr. The reaction mixture was diluted with ethyl acetate, and thediluted reaction mixture was washed with water, a 5% aqueous sodiumbicarbonate solution, and a 20% aqueous sodium chloride solution in thatorder and was dried over anhydrous magnesium sulfate. The solvent wasremoved by evaporation, and the residue was purified by columnchromatography on silica gel (2 to 5% methanol/methylene chloride) togive 5.14 g of2-bromo-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole.

¹H-NMR (CDCl₃) δ: 0.59-0.68 (6H, m), 0.88-0.94 (9H, m), 5.95 (1H, s),7.25 (1H, dd, J=4.7, 8.0 Hz), 7.41 (1H, s), 7.76 (1H, m), 7.83 (1H, s),8.50-8.52 (1H, dd, J=2.2, 4.7 Hz), 8.72 (1H, d, J=2.2 Hz)

Example 9 2-Bromo-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazole

Manganese dioxide (645 mg) was added to a solution of 645 mg of2-bromo-7-(pyridin-3-yl)hydroxymethylimidazo[5,1-b]thiazole in 12 ml ofmethylene chloride, and the mixture was stirred at room temperature for22 hr. The reaction mixture was filtered through Celite, followed bywashing with methylene chloride:methanol=10:1. The solvent was thenremoved by evaporation to give a crude solid. A hexane:ethyl acetate=3:1solution (10 ml) was added to this solid, and the mixture was stirred atroom temperature and was filtered to give 448 mg of2-bromo-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazole.

¹H-NMR (CDCl₃) δ: 7.43-7.47 (1H, m), 7.70 (1H, s), 8.04 (1H, s),8.78-8.85 (2H, m), 9.72-9.73 (1H, m)

Example 102-Bromo-7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazole

Acetic acid (0.86 ml) and 1.9 ml of dimethylhydrazine were added to asuspension of 1.89 g of2-bromo-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazole in 25 ml ofethanol, and, in a sealed tube, the mixture was heated to 80° C., andwas stirred for 18 hr. The reaction mixture was added to a diluteaqueous sodium bicarbonate solution to stop the reaction and wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium bicarbonate solution and saturated brine inthat order and was dried over anhydrous magnesium sulfate. The solventwas removed by evaporation, and the solid thus obtained was washed withan ethyl acetate:hexane=1:1 solution to give 1.41 g of2-bromo-7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazole.

¹H-NMR (CDCl₃) δ: 2.62 (6H, s), 7.31-7.35 (1H, m), 7.65 (1H, s), 7.92(1H, s), 7.98-8.01 (1H, m), 8.65 (1H, dd, J=1.6, 4.9 Hz), 8.88-8.90 (1H,m)

Example 11 2-Bromo-7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole

Methanol (50 ml) and 32 g of methyl orthoformate were added to 3.08 g of2-bromo-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazole, the mixture washeated to 50° C. for dissolution, and the solution was then cooled in anice-water bath. Sulfuric acid (5.4 ml) was added dropwise to thereaction mixture at that temperature, and the mixture was then heatedunder reflux for 18 hr. After heat release, the reaction mixture wasadded dropwise to 80 ml of a 2.5 N aqueous sodium hydroxide solutioncooled in an ice-water bath, and the mixture was extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate and wasthen concentrated by removing the solvent. The solid was then collectedby filtration to give 2.70 g of2-bromo-7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole.

¹H-NMR (CDCl₃) δ: 3.21 (6H, s), 7.24-7.29 (1H, m), 7.44 (1H, s), 7.84(1H, s), 7.90 (1H, ddd, J=1.9, 1.9, 8.0 Hz), 8.52 (1H, dd, J=1.6, 4.9Hz), 8.73 (1H, d, J=1.9 Hz)

Example 12 2-Bromo-7-diethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole

Ethanol (50 ml) and 44.5 g of ethyl orthoformate were added to 3.08 g of2-bromo-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazole. The mixture washeated to 50° C. for dissolution, and the solution was then cooled in anice-water bath. Sulfuric acid (5.4 ml) was added dropwise to thereaction mixture at that temperature, and the mixture was then heatedunder reflex for 18 hr. After standing to cool, the reaction mixture wasadded dropwise to 80 ml of a 2.5 N aqueous sodium hydroxide solutioncooled in an ice-water bath, and the mixture was extracted withmethylene chloride. The extract was dried over anhydrous magnesiumsulfate and was then concentrated by removing the solvent. Theconcentrate was purified by column chromatography on silica gel (5 to12% methanol/ethyl acetate) to give 1.29 g of2-bromo-7-diethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole.

¹H-NMR (CDCl₃) δ: 1.26 (6H, t, J=7.1 Hz), 3.37-3.45 (4H, m), 7.23-7.27(1H, m), 7.43 (1H, s), 7.81 (1H, s), 7.92 (1H, ddd, J=1.6, 1.6, 8.0 Hz),8.50 (1H, dd, J=1.6, 4.7 Hz), 8.73 (1H, dd, J=0.6, 2.2 Hz)

Example 132-Propionyl-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole

A solution of 5.14 g of2-bromo-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole in36 ml of tetrahydrofuran under an argon atmosphere was cooled to −60°C., 13.3 ml of a 0.89 M tetrahydrofuran solution of ethylmagnesiumbromide was added thereto, and the mixture was stirred for one hr.N-Methyl-N-methoxypropionamide (1.71 g) was added thereto at −30° C.,and the mixture was stirred at room temperature for 12 hr. A 20% aqueousammonium chloride solution was added to stop the reaction, and thereaction mixture was extracted with ethyl acetate. The extract waswashed with a saturated aqueous sodium bicarbonate solution andsaturated brine in that order and was then dried over anhydrousmagnesium sulfate. The solvent was removed by evaporation, and theresidue was purified by column chromatography on silica gel (3 to 6%methanol/methylene chloride) to give 3.88 g of2-propionyl-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole.

¹H-NMR (CDCl₃) δ: 0.56-0.82 (6H, m), 0.88-0.93 (9H, m), 1.25 (3H, t,J=7.28), 2.86 (2H, d, J=7.28), 5.98 (1H, s), 7.23-7.27 (1H, m),7.77-7.81 (1H, m), 7.97 (1H, s), 7.98 (1H, s), 8.51 (1H, dd, J=1.9, 4.7Hz), 8.73 (1H, d, J=1.9 Hz)

Example 142-Propionyl-7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazole

A solution of 1.75 g of2-bromo-7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazole in 10ml of tetrahydrofuran was cooled to −50° C. under an argon atmosphere,15.4 ml of a 0.89 M tetrahydrofuran solution of ethylmagnesium bromidewas added thereto, and the mixture was stirred for one hr.N-Methyl-N-methoxypropionamide (2.2 ml) was added thereto at −20° C.,and the mixture was stirred at room temperature for one hr. A 20%aqueous ammonium chloride solution was added to stop the reaction, andthe reaction mixture was extracted with ethyl acetate. The extract waswashed with saturated aqueous sodium bicarbonate solution and saturatedbrine in that order and was then dried over anhydrous magnesium sulfate.The solvent was removed by evaporation, and the solid was washed with anethyl acetate:hexane=2:1 solution to give 0.94 g of2-propionyl-7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazole.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.1 Hz), 2.92 (2H, q, J=7.1 Hz),7.31-7.35 (1H, m), 7.98 (1H, ddd, J=1.6, 1.6, 8.2 Hz), 8.87-8.88 (1H, m)

Example 157-Dimethoxy(pyridin-3-yl)methyl-2-propionylimidazo[5,1-b]thiazole

A solution of 10.63 g of2-bromo-7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole in 100 mlof tetrahydrofuran under an argon atmosphere was cooled to −50° C., 40ml of a 0.89 M tetrahydrofuran solution of ethylmagnesium bromide wasadded thereto, and the mixture was stirred for one hr.N-Methyl-N-methoxypropionamide (5.3 ml) was added thereto at −20° C.,and the mixture was stirred at room temperature for 6 hr. A saturatedaqueous ammonium chloride solution was added to stop the reaction, andthe reaction mixture was extracted with ethyl acetate. The organic layerwas washed with a saturated aqueous sodium bicarbonate solution andsaturated brine in that order and was then dried over anhydrousmagnesium sulfate. The solvent was removed by evaporation; and theresidue was purified by column chromatography on silica gel (5 to 15%methanol/ethyl acetate) to give a crude product of2-propionyl-7-(pyridin-3-yl)dimethoxymethylimidazo[5,1-b]thiazole. Asolution of this crude product in 200 ml of ethyl acetate was washedfour times with 100 ml of an aqueous 0.02 N hydrochloric acid solutionand was further washed with a 5% aqueous sodium bicarbonate solution anda 20% aqueous sodium chloride solution in that order to give 4.79 g of7-dimethoxy(pyridin-3-yl)methyl-2-propionylimidazo[5,1-b]thiazole.

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 2.88 (2H, q, J=7.1 Hz), 3.22(6H, s), 7.24-7.29 (1H, m), 7.88-7.92 (1H, m), 7.90 (1H, ddd, J=1.9,1.9, 8.2 Hz), 7.97 (1H, s), 8.02 (1H, s), 8.52 (1H, dd, J=1.6, 4.9 Hz),8.74-8.75 (1H, m)

Example 16(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

(a)(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

A 1 M tetrahydrofuran solution (5.2 ml) of lithiumbistrimethylsilylamide was added to a solution of 2.05 g of lithiumbromide in 10 ml of tetrahydrofuran under an argon atmosphere, and themixture was cooled to −78° C. A solution of 0.95 g of2-propionyl-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole in 4.7 ml of tetrahydrofuran was addedthereto, and the mixture was stirred at that temperature for one hr. Asolution of 0.81 g of(3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-onein 3.8 ml of tetrahydrofuran was added thereto, and the mixture wasstirred at that temperature for 2 hr. A 10% aqueous citric acid solutionwas added to the reaction mixture to stop the reaction, and the reactionmixture was extracted with ethyl acetate. The extract was washed with asaturated aqueous sodium bicarbonate solution and saturated brine inthat order and was then dried over anhydrous magnesium sulfate. Theextract was then concentrated by removing the solvent, and theconcentrate was purified by column chromatography on silica gel (5 to10% methanol/methylene chloride) to give 0.80 g of a crude product of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

(b)(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-hydroxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

The crude product (0.80 g) of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-oneprepared in step (a) was dissolved in 7 ml of methanol, and the solutionwas cooled in an ice bath. A 1 N aqueous hydrochloric acid solution (2.6ml) was added thereto, and the mixture was stirred at that temperaturefor 1 hr 40 min. The reaction mixture was neutralized with a diluteaqueous sodium bicarbonate solution and was extracted with methylenechloride. The extract was washed with a saturated aqueous sodiumbicarbonate solution and saturated brine in that order and was thendried over anhydrous magnesium sulfate. The extract was concentrated byremoving the solvent to give a crude product of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-hydroxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

(c)(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

The crude product of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-hydroxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-oneprepared in step (b) was dissolved in 13.5 ml of methylene chloride and1.5 ml of methanol, 1 g of manganese dioxide was added thereto, and themixture was stirred at room temperature for 4 hr. The reaction mixturewas filtered through Celite, and the solvent was removed by evaporationto give 0.63 g of a crude product of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.This crude product (0.63 g) was crystallized from ethyl acetate to give0.38 g of (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

¹H-NMR (CDCl₃) δ: 0.06 (3H, s), 0.08 (3H, s), 0.87 (9H, s), 1.17 (3H, d,J=6.3 Hz), 1.39 (3H, d, J=6.9 Hz), 2.92 (1H, dd, J=2.2, 4.4 Hz),3.34-3.43 (1H, m), 4.02 (1H, dd, J=4.7, 6.0 Hz), 4.14-4.23 (1H, m), 6.14(1H, s), 7.43-7.48 (1H, m), 8.20 (1H, s), 8.26 (1H, s), 8.77-8.83 (2H,m), 9.73-9.75 (1H, m)

Example 17(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

Tetrahydrofuran (1 ml) was added to 1.1 ml of a 1 M tetrahydrofuransolution of lithium bistrimethylsilylamide under an argon atmosphere,and the mixture was cooled to −78° C. A solution of 0.16 g of2-propionyl-7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazole in2.5 ml of tetrahydrofuran was added thereto, and the mixture was stirredat that temperature for 30 min. A solution of 0.18 g of(3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-onein 1 ml of tetrahydrofuran was added thereto, and the mixture wasstirred at that temperature for 3.5 hr. A 10% aqueous citric acidsolution was added to the reaction mixture to stop the reaction, and thereaction mixture was extracted with ethyl acetate. The extract waswashed with a saturated aqueous sodium bicarbonate solution andsaturated brine in that order. The extract was then dried over anhydrousmagnesium sulfate. The solvent was removed by evaporation, and theresidue was purified by thin layer chromatography (developed with 10%methanol/methylene chloride) to give 0.16 g of a crude product of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.This crude product was purified by Cosmosil 40C₁₈ reverse phase columnchromatography (a 60% aqueous acetonitrile solution) to give 72.3 mg of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

¹H-NMR (CDCl₃) δ: 0.07 (3H, s), 0.08 (3H, s), 0.88 (9H, s), 1.19 (3H, d,J=6.3 Hz), 1.38 (3H, d, J=7.1 Hz), 2.63 (6H, s), 2.96 (1H, dd, J=2.2,4.4 Hz), 3.31-3.41 (1H, m), 4.01 (1H, dd, J=2.2, 4.9 Hz), 4.15-4.25 (1H,m), 6.12 (1H, s), 7.34 (1H, ddd, J=0.8, 4.9, 8.0 Hz), 7.99 (1H, ddd,J=2.2, 2.2, 8.0 Hz), 8.10 (1H, s), 8.25 (1H, s), 8.65 (1H, dd, J=2.2,4.9 Hz), 8.88 (1H, dd, J=0.8, 2.2 Hz)

Example 18(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

Tetrahydrofuran (4 ml) was added to 4.4 ml of a 1 M tetrahydrofuransolution of lithium bistrimethylsilylamide under an argon atmosphere,and the mixture was cooled to −78° C. A solution of 0.70 g of7-dimethoxy(pyridin-3-yl)methyl-2-propionylimidazo[5,1-b]thiazole in 4ml of tetrahydrofuran was added thereto, and the mixture was stirred atthat temperature for 30 min. A solution of 0.69 g of(3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-onein 2.4 ml of tetrahydrofuran was added thereto, and the mixture wasstirred at that temperature for 13 hr. A 10% aqueous citric acidsolution was added to the reaction mixture to stop the reaction, and thereaction mixture was extracted with ethyl acetate. The extract waswashed with a saturated aqueous sodium bicarbonate solution andsaturated brine in that order and was then dried over anhydrousmagnesium sulfate. The solvent was removed by evaporation, and theresidue was purified by column chromatography on silica gel (7.5 to 12%methanol/ethyl acetate) to give 0.21 g of a crude product of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.This crude product was purified by Cosmosil 40C₁₈ reverse phase columnchromatography (a 60% aqueous acetonitrile solution) to give 64.5 mg of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

¹H-NMR (CDCl₃) δ: 0.06 (3H, s), 0.08 (3H, s), 0.87 (9H, s), 1.17 (3H, d,J=6.3 Hz), 1.36 (3H, d, J=6.9 Hz), 2.94 (1H, dd, J=1.9, 4.1 Hz), 3.23(6H, s), 3.30-3.39 (1H, m), 3.99 (1H, dd, J=1.9, 4.9 Hz), 4.15-4.23 (1H,m), 6.10 (1H, s), 7.35 (1H, dd, J=4.9, 8.0 Hz), 7.96-8.04 (1H, m), 8.01(1H, s), 8.09 (1H, s), 8.54 (1H, dd, J=1.3, 4.9 Hz), 8.74 (1H, d, J=1.9Hz)

Example 19(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

(a)(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

A 1 M tetrahydrofuran solution (11 ml) of lithium bistrimethylsilylamidewas added to a solution of 0.64 g of lithium chloride in 10 ml oftetrahydrofuran under an argon atmosphere, and the mixture was cooled to−78° C. A solution of 1.66 g of7-dimethoxy(pyridin-3-yl)methyl-2-propionylimidazo[5,1-b]thiazole in 5ml of tetrahydrofuran was added thereto, and the mixture was stirred atthat temperature for one hr. A solution of 1.72 g of(3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-onein 5 ml of tetrahydrofuran was added thereto, and the mixture wasstirred at that temperature for 1.5 hr. The reaction mixture was addedto a mixed liquid composed of 50 ml of a 10% aqueous citric acidsolution and 25 ml of tetrahydrofuran cooled in an ice-water bath tostop the reaction, and the reaction mixture was extracted with ethylacetate. The extract was washed with a 0.05 N aqueous hydrochloric acidsolution, a saturated aqueous sodium bicarbonate solution and saturatedbrine in that order and was then dried over anhydrous magnesium sulfate.The extract was concentrated by removing the solvent, and theconcentrate was analyzed by HPLC (Cosmosil 5C₁₈-MS, 4.6×150 mm, a 70%aqueous acetonitrile solution). As a result, it was found that the yieldof(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxymethyl(pyridin-3-yl)imidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-onewas 1.17 g. An ethyl acetate:hexane=1:3 solution (20 ml) was added tothe mixture, and the mixture was stirred. The precipitated solid wascollected by filtration to give 1.00 g of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.The solid was analyzed by NMR. The results were in agreement with theresults of analysis in Example 18.

(b)(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one(2.02 g) prepared in step (a) was dissolved in 40 ml of 1,4-dioxane atroom temperature, and 40 ml of dimethyl sulfoxide and 6 ml of water wereadded in that order to the solution. The temperature of this solutionwas raised to 104° C., and the solution was stirred at that temperaturefor 2 days. After the completion of the reaction, the solution wascooled to room temperature, and dioxane was removed by evaporation underthe reduced pressure. The residue was diluted with a mixed solutioncomposed of ethyl acetate and tetrahydrofuran, 20% brine was then addedthereto, and the reaction mixture was extracted with a mixed solutioncomposed of ethyl acetate and tetrahydrofuran. The organic layer waswashed with 20% brine and was then dried over magnesium sulfate. Thesolvent was removed by evaporation, and the residue was crystallizedfrom butyl acetate-isopropylether-heptane to give 1.64 g of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.This product was analyzed by NMR. The results were in agreement with theresults of analysis in Example 16-(c).

Example 20(3S,4R)-3-[(1R)-1-Hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

A 5 N aqueous hydrochloric acid solution (2 ml) was added to a solutionof 0.56 g of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxymethyl(pyridin-3-yl)imidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-onein 2 ml of methanol, and the mixture was stirred at 50° C. for one hr.The reaction mixture was diluted with water, and the diluted solutionwas extracted with methylene chloride. The organic layer was extractedwith 10 ml of a 0.5 N aqueous hydrochloric acid solution. The aqueouslayers were combined and were neutralized with a 5 N aqueous sodiumhydroxide solution, and the resultant precipitate was collected byfiltration to give 0.34 g of(3S,4R)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

¹H-NMR (DMSO-d₆) δ: 0.95 (3H, d, J=6.3 Hz), 1.23 (3H, d, J=6.6 Hz), 2.89(1H, dd, J=1.6, 5.2 Hz), 3.61-3.82 (3H, m), 4.74 (1H, d, J=5.2 Hz), 7.62(1H, dd, J=4.9, 8.0 Hz), 8.24 (1H, s), 8.64 (1H, s), 8.72 (1H, ddd,J=1.9, 1.9, 8.0 Hz), 8.80 (1H, dd, J=1.9, 4.9 Hz), 9.37 (1H, s), 9.57(1H, d, J=1.9 Hz)

Example 21(3S,4R)-3-[(1R)-1-(Triethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

Imidazole (0.15 g) and 0.36 ml of triethylsilylchloride were added to asolution of 0.32 g of(3S,4R)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one in 3.2 ml ofdimethylformamide under ice cooling, and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was diluted with 80 ml ofethyl acetate, and the diluted reaction mixture was washed three timeswith 20 ml of a 10% aqueous sodium chloride solution and was then washedwith an a saturated aqueous sodium chloride solution and was dried overanhydrous magnesium sulfate. The solvent was removed by evaporation, theresultant solid was suspended in 4 ml of a hexane:ethyl acetate=1:1solution and was collected by filtration to give 0.33 g of(3S,4R)-3-[(1R)-1-(triethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

¹H-NMR (CDCl₃) δ: 0.60 (6H, q, J=7.7 Hz), 0.94 (9H, t, J=7.7 Hz), 1.20(3H, d, J=6.3 Hz), 1.40 (3H, d, J=7.1 Hz), 2.93 (1H, dd, J=1.9, 5.2 Hz),3.35-3.45 (1H, m), 4.00 (1H, dd, J=2.2, 4.7 Hz), 4.14-4.22 (1H, m), 6.14(1H, s), 7.44-7.50 (1H, m), 8.20 (1H, s), 8.28 (1H, s), 8.27-8.33 (2H,m), 9.75 (1H, m)

Example 22(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxymethyl(pyridin-3-yl)imidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

Methylene chloride (2 ml) was added to 0.69 g of tin(II)trifluoromethanesulfonate under an argon atmosphere, and the mixture wascooled to −20° C. A solution of 0.25 g of2-propionyl-7-(pyridin-3-yl)dimethoxymethylimidazo[5,1-b]thiazole in 1.5ml of methylene chloride and 0.12 ml of N-ethylpiperidine were addedthereto, and the mixture was stirred for 2 hr. A solution of 0.14 g of(3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-onein 1 ml of methylene chloride was added at 0° C., and the mixture wasstirred at room temperature for one hr. A saturated aqueous sodiumbicarbonate solution was added to the reaction mixture to stop thereaction, and the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with a 5% aqueous sodium bicarbonate solutionand a 20% aqueous sodium chloride solution in that order and was driedover anhydrous magnesium sulfate. The solvent was removed byevaporation, and the residue was analyzed by HPLC (Cosmosil 5C₁₈-MS,4.6×150 mm, a 700% aqueous acetonitrile solution). As a result, it wasfound that the yield of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-onewas 45 mg. The results of analysis by NMR were in agreement with theresults of analysis in Example 18.

Example 23(3S,4R)-1-Allyloxyoxalyl-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

Diisopropylethylamine (0.45 ml) and 0.32 ml of allyloxyoxalyl chloridewere added in that order under an argon atmosphere to a solution of 0.66g of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-onein 6.4 ml of methylene chloride, and the mixture was stirred at roomtemperature for 10 min. The reaction mixture was diluted with ethylacetate, and the diluted reaction mixture was washed with a saturatedaqueous sodium bicarbonate solution and saturated brine in that orderand was then dried over anhydrous magnesium sulfate. The solvent wasremoved by evaporation, and the resultant solid was washed with ethylacetate to give 0.57 g of(3S,4R)-1-allyloxyoxalyl-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridine-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

¹H-NMR (CDCl₃) δ: 0.02 (3H, s), 0.08 (3H, s), 0.85 (9H, s), 1.25 (3H, d,J=6.3 Hz), 1.38 (3H, d, J=7.1 Hz), 3.71 (1H, dd, J=3.0, 3.0 Hz),4.20-4.30 (1H, m), 4.30-4.40 (1H, m), 4.50-4.55 (1H, m), 4.57-4.63 (2H,m), 5.15-5.24 (2H, m), 5.65-5.79 (1H, m), 7.44-7.48 (1H, m), 8.18 (1H,s), 8.21 (1H, s), 8.78-8.82 (2H, m), 9.73-9.75 (1H, m)

Example 24 Allyl(1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate

A 30% hexane solution (0.19 ml) of diethyl methylphosphonite was addedto a solution of 62.4 mg of(3S,4R)-1-allyloxyoxalyl-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-onein 1 ml of tetrahydrofuran under an argon atmosphere, and the mixturewas stirred at room temperature for one hr and was then stirred at 40 to50° C. for 1.5 hr. Isopropyl alcohol (1 ml) was added to the reactionmixture, and the solvent was removed by evaporation, followed byrepetition of this procedure three times. Thereafter, 2 ml of isopropylalcohol was added thereto, and the mixture was stirred at 60° C. for onehr. The solvent was removed by evaporation, and the residue was purifiedby thin layer chromatography (developed with ethyl acetate) to give 33.6mg of allyl (1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate.

¹H-NMR (CDCl₃) δ: 0.10 (3H, s), 0.11 (3H, s), 0.91 (9H, s), 1.27 (3H, d,J=5.8 Hz), 1.29 (3H, d, J=6.6 Hz), 3.33 (1H, dd, J=2.7, 5.2 Hz),3.42-3.52 (1H, m), 4.26-4.36 (1H, m), 4.39 (1H, dd, J=2.7, 9.9 Hz),4.70-4.86 (2H, m), 5.27-5.49 (2H, m), 5.91-6.03 (1H, m), 7.45 (1H, dd,J=4.7, 7.7 Hz), 8.10 (1H, s), 8.61 (1H, s), 8.77-8.85 (2H, m), 9.71 (1H,m)

Example 25(3S,4R)-1-Allyloxyoxalyl-3-[(1R)-1-hydroxyethyl)-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

A boron trifluoride diethyl ether complex (0.59 ml) was added to asuspension of 0.59 g of(3S,4R)-1-allyloxyoxalyl-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-onein 5 ml of acetonitrile under an argon atmosphere, and the mixture wasstirred at room temperature for 22 hr. The reaction mixture was added toa mixed liquid composed of ethyl acetate and a dilute aqueous sodiumbicarbonate solution with stirring to stop the reaction, and the organiclayer was separated. The organic layer was washed with a saturatedaqueous sodium bicarbonate solution and saturated brine in that order.The solvent was removed by evaporation to give 0.51 g of(3S,4R)-1-allyloxyoxalyl-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

¹H-NMR (CDCl₃) δ: 1.37 (3H, d, J=6.3 Hz), 1.42 (3H, d, J=7.1 Hz), 3.74(1H, d, J=3.3, 5.2 Hz), 4.19-4.35 (2H, m), 4.49-4.52 (1H, m), 4.62-4.64(2H, m), 5.21-5.30 (2H, m), 5.69-5.82 (1H, m), 7.45-7.50 (1H, m), 8.17(1H, s), 8.28 (1H, s), 8.78-8.82 (2H, m), 8.73-8.74 (1H, m)

Example 26 Allyl(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate

A 30% hexane solution (0.19 ml) of diethyl methylphosphonite was addedto a solution of 51 mg of(3S,4R)-1-allyloxyoxalyl-3-[(1R)-1-hydroxyethyl)-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-onein 1 ml of tetrahydrofuran under an argon atmosphere, and the mixturewas stirred at room temperature for 2.5 hr. Isopropyl alcohol (1 ml) wasadded to the reaction mixture, and the solvent was removed byevaporation, followed by repetition of this procedure three times.Thereafter, 2 ml of isopropyl alcohol was added thereto, and the mixturewas heated under reflux for 2 hr. The solvent was removed byevaporation, and the residue was purified by thin layer chromatography(developed with 100/0 methanol/methylene chloride) to give 26.6 mg ofallyl(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate.

¹H-NMR (CDCl₃) δ: 1.32 (3H, d, J=7.1 Hz), 1.40 (3H, d, J=6.3 Hz), 3.38(1H, dd, J=2.7, 6.9 Hz), 3.52-3.60 (1H, m), 4.26-4.35 (1H, m), 4.40 (1H,dd, J=2.7, 9.6 Hz), 4.71-4.91 (2H, m), 5.28-5.50 (2H, m), 5.92-6.05 (1H,m), 7.44-7.49 (1H, m), 8.11 (1H, s), 8.61 (1H, s), 8.78 (1H, dd, J=1.6,4.7 Hz), 8.84 (1H, ddd, J=1.9, 1.9, 8.0 Hz), 9.70-9.71 (1H, m)

Example 27(3S,4R)-3-[(1R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-one

(a)(3S,4R)-3-[(1R)-1-(t-Butyldimethylsilyloxy)ethyl-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[[(4-nitrobenzyloxy)carbonyl]hydroxymethyl]]azetidin-2-one

4-Nitrobenzyl glyoxylate monohydrate (0.14 g) was added to a solution of0.26 g of(3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-onein 15 ml of toluene, and the mixture was heated under reflux for 1.5 hr.The insolubles were removed, and the solvent was removed by evaporationto give 0.23 g of a crude product of(3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[[(4-nitrobenzyloxy)carbonyl]hydroxymethyl]azetidin-2-one.

(b)(3S,4R)-3-[(1R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-one

Pyridine (0.1 ml) was added to a solution of 0.23 g of the crude productof(3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[[(4-nitrobenzyloxy)carbonyl]hydroxymethyl]azetidin-2-onein 2 ml of tetrahydrofuran under an argon atmosphere, and the mixturewas cooled to −20° C. Thionyl chloride (0.09 ml) was added thereto, andthe mixture was stirred at that temperature for one hr. The reactionmixture was diluted with ethyl acetate, and the diluted reaction mixturewas washed with water and saturated brine and was then dried overanhydrous magnesium sulfate. The solvent was removed by evaporation togive a crude product of(3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[[(4-nitrobenzyloxy)carbonyl]chloromethyl]azetidin-2-one.Triphenylphosphine (0.26 g) and 0.05 g of potassium iodide were added toa solution of this crude product in 2 ml of dimethylformamide, and themixture was stirred at 60° C. for one hr. The reaction mixture wasdiluted with ethyl acetate, and the diluted reaction mixture was washedwith water and saturated brine and was then dried over anhydrousmagnesium sulfate. The solvent was removed by evaporation, and theresidue was purified by thin layer chromatography (developed with 10%methanol/ethyl acetate) to give 0.19 g of(3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-one.

¹H-NMR (CDCl₃) δ: −0.90-0.00 (6H, m), 0.75-0.85 (9H, m), 0.90-1.00 (3H,m), 1.40-1.60 (3H, m), 2.60-2.70 (2H, m), 2.70-2.90 (2H, m), 4.80-4.95(2H, m), 6.65-6.75 (2H, m), 7.4-7.9 (18H, m), 8.15-8.25 (1H, m),8.70-8.95 (3H, m), 9.70-9.80 (1H, m)

Example 28 (4-Nitrobenzyl)(1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate

A solution of 54.6 mg of(3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-onein 2 ml of toluene was heated under reflux for 2.5 hr. The solvent wasremoved by evaporation, and the residue was purified by thin layerchromatography (developed with 5% methanol/ethyl acetate) to give 28.3mg of (4-nitrobenzyl)(1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate.

¹H-NMR (CDCl₃) δ: 0.09 (3H, s), 0.11 (3H, m), 0.87 (9H, s), 1.28 (3H, d,J=6.3 Hz), 1.31 (3H, d, J=7.1 Hz), 3.36 (1H, dd, J=4.7, 7.7 Hz),3.45-3.58 (1H, m), 4.28-4.38 (1H, m), 4.4 (1H, dd, J=3.0, 9.9 Hz), 5.28(1H, d, J=13.7 Hz), 5.50 (1H, d, J=13.7 Hz), 7.43-7.49 (1H, m), 7.68(2H, d, J=8.8 Hz), 8.10 (1H, s), 8.24 (2H, d, J=8.8 Hz), 8.58 (1H, s),8.78 (1H, dd, J=1.6, 4.9 Hz), 8.83 (1H, ddd, J=1.6, 1.6, 8.0 Hz), 9.71(1H, dd, J=0.8, 1.6 Hz)

Example 29(3S,4R)-3-[(1R)-1-Hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-one

A 5 N aqueous hydrochloric acid solution (1 ml) was added to a solutionof 72.4 mg of(3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)-methyl]azetidin-2-onein 2 ml of methanol, and the mixture was stirred at room temperature for2 hr. The reaction mixture was neutralized with saturated aqueous sodiumbicarbonate solution and was extracted with ethyl acetate. The organiclayer was washed with saturated brine and was dried over anhydrousmagnesium sulfate. The solvent was removed by evaporation, and theresidue was purified by thin layer chromatography (developed with 10%methanol/methylene chloride) to give 46.9 mg of(3S,4R)-3-[(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-one.

¹H-NMR (CDCl₃) δ: 0.9-1.0 (3H, m), 1.5-1.7 (3H, m), 2.3-3.1 (3H, m),3.60-3.70, 4.0-4.2 (1H, m), 4.7-5.0, 5.1-5.4 (2H, m), 6.69 (2H, d, J=6.8Hz), 7.4-7.8 (18H, m), 8.13-8.27 (2H, m), 8.78 (2H, m), 9.71 (1H, s).

Example 30 (4-Nitrobenzyl)(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate

A solution of 46.9 mg of (3S,4R)-3-[(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)-methyl]azetidin-2-one in 1 ml of toluenewas heated under reflux for 3 hr. The solvent was removed byevaporation, and the residue was purified by thin layer chromatography(developed with 10% methanol/methylene chloride) to give 23.1 mg of(4-nitrobenzyl)(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate.

¹H-NMR (CDCl₃) δ: 1.33 (3H, d, J=7.3 Hz), 1.41 (3H, d, J=6.1 Hz), 3.43(1H, dd, J=3.0, 6.4 Hz), 3.60 (1H, m), 4.35 (1H, m), 4.49 (1H, dd,J=2.9, 9.7 Hz), 5.22 (1H, d, J=13.9 Hz), 5.50 (1H, d, J=13.6 Hz), 7.46(1H, ddd, J=0.7, 4.9, 8.1 Hz), 7.67 (2H, d, J=8.8 Hz), 8.11 (1H, s),8.17 (2H, d, J=8.8 Hz), 8.53 (1H, s), 8.76 (1H, dd, J=1.7, 4.8 Hz), 8.84(1H, dt, J=2.0, 7.9 Hz), 9.69 (1H, dd, J=0.7, 2.2 Hz)

Example 31(3S,4R)-1-[Allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one

A solution of 0.12 g of2-iodo-7-triethylsilyloxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole in 2ml of tetrahydrofuran was cooled to −60° C., 0.31 ml of a 0.89 Mtetrahydrofuran solution of ethylmagnesium bromide was added thereto,and the mixture was stirred at that temperature for one hr. A solutionof 0.23 g of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-(4-dimethylaminobenzoyl-oxycarbonyl)ethyl]azetidin-2-onein 0.7 ml of tetrahydrofuran was added to the reaction mixture, and themixture was stirred at room temperature for 3 hr. The reaction mixturewas added to a 20% aqueous ammonium chloride solution, and the mixturewas extracted twice with 20 ml of ethyl acetate. The organic layers werecombined and were washed with a mixed liquid composed of 2 ml of 1 Nhydrochloric acid and 18 ml of 20% brine, a 5% aqueous sodiumbicarbonate solution (20 ml) and 20% brine (20 ml) in that order and wasthen dried over anhydrous magnesium sulfate. The solvent was removed byevaporation, and the residue was purified by chromatography on silicagel (methylene chloride:methanol=20:1) to give 94 mg of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-[7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one.

¹H-NMR (CDCl₃) δ: −0.03 (3H, s), −0.02 (3H, s), 0.68 (6H, m), 0.85 (9H,2s), 0.94 (13H, m), 1.55 (3H, m), 2.63-2.87 (2H, m), 3.80-3.99 (1H, m),4.24 (1H, m), 4.62-4.74 (2H, m), 5.19-5.27 (2H, m), 6.03 (1H, m), 7.29(1H, m), 7.56-7.86 (16H, m), 8.03 (1H, m), 8.55 (1H, m), 8.78 (1H, m).

MS (FAB⁺) m/z 987 (M⁺)

Example 32 Allyl(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate

(a) (3S,4R)-1-[Allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one

A solution of 0.24 g of2-bromo-7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole intetrahydrofuran (2 ml) was cooled to −60° C., 0.84 ml of a 0.89 Mtetrahydrofuran solution of ethylmagnesium bromide was added thereto,and the mixture was stirred at that temperature for one hr. A solutionof 0.60 g of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-(4-dimethylaminobenzoyl-oxycarbonyl)ethyl]azetidin-2-onein 1 ml of tetrahydrofuran was added to the reaction mixture, and themixture was stirred at room temperature for 4 hr. The reaction mixturewas added to a 20% aqueous ammonium chloride solution, and the mixturewas extracted twice with ethyl acetate (20 ml). The organic layers werecombined, were washed with 10% brine (20 ml), and was dried overanhydrous magnesium sulfate. The solvent was removed by evaporation, andthe residue was purified by chromatography on silica gel (methylenechloride:methanol=20:1) to give 0.37 g of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one.

¹H-NMR (CDCl³) δ: −0.06 (3H, s), −0.05 (3H, s), 0.81 (9H, s), 0.90 (3H,2s), 1.49 (3H, m), 2.39 (1H, m), 2.64-2.86 (1H, m), 3.21 (3H, 2s),3.76-4.04 (1H, m), 4.18 (1H, m), 4.59 (1H, m), 4.67 (1H, m), 5.12-5.43(2H, m), 6.04 (1H, m), 7.26 (1H, m), 7.52-7.81 (15H, m), 7.90 (1H, m),7.95-8.04 (2H, m), 8.51 (1H, m), 8.76 (1H, m).

MS (FAB⁺) m/z 917 (M⁺)

(b) Allyl(1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate

Toluene (20 ml) was added to 1.90 g of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one,and the mixture was heated under reflux for 3.5 hr. The reaction mixturewas concentrated by removing the solvent, and the concentrate waspurified by column chromatography on silica gel (eluted with 4%methanol/ethyl acetate) to give 1.04 g of allyl(1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-[7-dimethoxy(pyridin-3-yl)methylimidazo-[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate.

¹H-NMR (CDCl³) δ: 0.30 (6H, s), 0.91 (9H, s), 1.27 (3H, d, J=4.4 Hz),1.29 (3H, d, J=5.5 Hz), 3.22 (3H, s), 3.23 (3H, s), 3.30 (1H, dd, J=2.7,5.5 Hz), 3.35-3.47 (1H, m), 4.23-4.33 (2H, m), 4.68-4.88 (2H, m),5.25-5.30 (1H, m), 5.40-5.50 (1H, m), 5.90-6.05 (1H, m), 7.23-7.31 (1H,m), 7.90 (1H, s), 7.90-7.95 (1H, m), 8.31 (1H, s), 8.51 (1H, dd, J=1.6,4.7 Hz), 8.75 (1H, d, J=2.2 Hz)

(c) Allyl(1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate

Dimethyl sulfoxide (2 ml) and 1 ml of water were added to a solution of0.28 g of allyl(1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylatein 12 ml of dioxane, and the mixture was stirred at 90° C. for 36 hr.The reaction mixture was diluted with 50 ml of ethyl acetate, and thediluted reaction mixture was washed three times with 25 ml of water andthen with 100% brine. The organic layer was dried over anhydrousmagnesium sulfate. The solvent was removed by evaporation, and theresidue was purified by column chromatography on silica gel (eluted withethyl acetate) to give 0.16 g of allyl(1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate.This product was analyzed by NMR. The results were in agreement with theresults of analysis in Example 24.

(d) Allyl(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate

Acetic acid (0.23 ml) and 0.72 ml of a 1 M tetrahydrofuran solution oftetrabutylammonium fluoride was added to a solution of 0.14 g of allyl(1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylatein 2 ml of tetrahydrofuran, and the mixture was stirred at roomtemperature for 36 hr. The reaction mixture was diluted with 50 ml ofethyl acetate, and the diluted reaction solution was washed with a 50%aqueous sodium bicarbonate solution and 10% brine in that order. Theorganic layer was dried, and the solvent was then removed byevaporation. The resultant crude product was purified by columnchromatography on silica gel (eluted with 100% methanol/ethyl acetate)to give 60.3 mg of allyl(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate.This product was analyzed by NMR. The results were in agreement with theresults of analysis in Example 26.

Example 33(3S,4R)-1-Allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one

In the same manner as in Example 32, 66 mg of the title compound wasprepared from 0.25 g of2-bromo-7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole and 0.63 gof(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-(pivaloyloxycarbonyl)ethyl]azetidin-2-one.

Example 34 (3S,4R)-1-[Allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one

In the same manner as in Example 32, 0.27 g of the title compound wasprepared from 0.25 g of2-bromo-7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole and 0.66 gof (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-(4-methoxybenzoyloxycarbonyl)-ethyl]azetidin-2-one.

Example 35 (3S,4R)-1-[Allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one

In the same manner as in Example 32, 0.51 g of the title compound wasprepared from 0.35 g of2-bromo-7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole and 1.01 gof (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-(4-diethylaminobenzoyloxy-carbonyl)ethyl]azetidin-2-one.

Example 36 (3S,4R)-1-[Allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-[(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one

Methanol (0.5 ml) was added to and dissolved in 113 mg of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-(7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl)-2-oxoethyl]azetidin-2-one,0.5 ml of 5 N hydrochloric acid was added thereto, and the mixture wasstirred at 45° C. for one hr. The reaction mixture was cooled to roomtemperature, was then neutralized by the addition of a 5% aqueous sodiumbicarbonate solution, and was extracted with 20 ml of ethyl acetate. Theaqueous layer was reextracted with 10 ml of ethyl acetate. The organiclayers were combined, were washed with 10% brine, and were dried overanhydrous magnesium sulfate. The solvent was removed by evaporation, andthe residue was purified by chromatography on silica gel (methylenechloride:methanol=15:1) to give 86 mg of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one.

¹H-NMR (CDCl₃) δ: 0.96 (3H, d, J=6.1 Hz), 1.67 (3H, d, J=6.9 Hz),2.43-3.02 (3H, m), 3.86-4.18 (2H, m), 4.53-4.70 (2H, m), 5.08-5.53 (2H,m), 6.13 (1H, m), 7.45 (1H, m), 7.51-7.79 (16H, m), 8.23 (1H, m), 8.79(2H, m), 9.71 (1H, m).

MS (FAB⁺) m/z 757 (M⁺)

Example 37 (3S,4R)-1-[Allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-diethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

A solution of 0.38 g of2-bromo-7-diethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole in 2 ml oftetrahydrofuran was cooled to −35° C., 1.2 ml of a 0.89 Mtetrahydrofuran solution of ethylmagnesium bromide was added thereto,and the mixture was stirred at that temperature for 45 min. The reactionmixture was cooled to −70° C., a solution of 0.88 g of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-(4-diethylaminobenzoyloxy-carbonyl)ethyl]azetidin-2-one in 1.5 ml of tetrahydrofuranwas added thereto, and the temperature was raised from −45° C. to roomtemperature with stirring over a period of 4 hr. A saturated aqueousammonium chloride solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith dilute hydrochloric acid, a dilute aqueous sodium bicarbonatesolution, and a saturated aqueous sodium chloride solution in that orderand was dried over anhydrous magnesium sulfate. The solvent was removedby evaporation, and the residue was purified by column chromatography onsilica gel (5 to 10% methanol/ethyl acetate) to give 0.58 g of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-diethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

¹H-NMR (CDCl₃) δ: −0.06 (3H, s), −0.04 (3H, s), 0.81 (9H, s), 0.8-0.9(3H, m), 1.2-1.3 (6H, m), 1.4-1.6 (3H, m), 2.6-2.7 (1H, m), 2.7-3.0 (2H,m), 3.3-3.5 (4H, m), 3.7-4.0 (1H, m), 4.1-4.3 (1H, m), 4.5-4.7 (2H, m),5.1-5.3 (1H, m), 5.3-5.5, 6.0-6.1 (1H, m), 7.2-7.3 (1H, m), 7.5-7.7 (9H,m), 7.7-7.9 (6H, m), 7.9-8.0 (2H, m), 8.45-8.55 (2H, m), 8.7-8.8 (1H, m)

Example 38 (3S,4R)-1-[Allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

A 5 N aqueous hydrochloric acid solution (2.5 ml) was added to 2.5 ml ofa methanol solution of 0.53 g of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-diethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-oneat room temperature, and the mixture was stirred at 50° C. for one hr.The reaction mixture was neutralized with a dilute aqueous sodiumbicarbonate solution and was extracted with ethyl acetate. The organiclayer was washed with a 5% aqueous sodium bicarbonate solution and a 20%aqueous sodium chloride solution in that order and was dried overanhydrous magnesium sulfate. The solvent was removed by evaporation, andthe residue was purified by column chromatography on silica gel (2 to7.5% methanol/methylene chloride) to give 0.41 g of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.This product was analyzed by NMR. The results were in agreement with theresults of analysis in Example 36.

Example 39 Allyl(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate

Toluene (20 ml) was added to 0.76 g of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one,and the mixture was heated under reflux for 2 hr. The reaction solutionwas concentrated by removing the solvent, and the concentrate waspurified by column chromatography on silica gel (eluted with 5 to 10%methanol/ethyl acetate). The eluate containing the contemplated productwas concentrated, and the resultant solid was washed with a hexane:ethylacetate=1:1 solution to give 0.38 g of allyl(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate.This product was analyzed by NMR. The results were in agreement with theresults of analysis in Example 26.

Example 40 (3S,4R)-1-[Allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

A solution of 0.18 g of2-bromo-7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazole in 2ml of tetrahydrofuran was cooled in an ice-water bath, 0.6 ml of a 0.89M tetrahydrofuran solution of ethylmagnesium bromide was added thereto,and the mixture was stirred at that temperature for one hr. The reactionmixture was cooled to −60° C., 1.2 ml of a tetrahydrofuran solution of0.48 g of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-(4-dimethylaminobenzoyloxy-carbonyl)ethyl]azetidin-2-onewas added thereto, and the temperature was raised from −45° C. to roomtemperature with stirring over a period of 4 hr. A saturated aqueousammonium chloride solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith dilute hydrochloric acid, a dilute aqueous sodium bicarbonatesolution, and a saturated aqueous sodium chloride solution in that orderand was dried over anhydrous magnesium sulfate. The solvent was removedby evaporation, and the residue was purified by column chromatography onsilica gel (5 to 7% methanol/methylene chloride) to give 0.21 g of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

¹H-NMR (CDCl₃) δ: −0.06 (3H, s), −0.02 (3H, m), 0.83 (9H, s), 0.9-1.0(3H, m), 1.5-1.6 (3H, m), 2.59 (6H, s), 2.5-3.0 (3H, m), 3.8-4.1 (1H,m), 4.1-4.4 (2H, m), 4.6-4.8 (2H, m), 5.2-5.4 (1H, m), 7.3-7.4 (1H, m),7.5-7.7 (9H, m), 7.8-7.9 (6H, m), 8.0-8.1 (1H, m), 8.1-8.3 (2H, m),8.65-8.75 (1H, m), 8.9-9.0 (1H, m)

Example 41 Allyl(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate

A 5 N aqueous hydrochloric acid solution (1 ml) was added to a solutionof 0.21 g of (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)dimethylhydrazonoylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-onein 1 ml of methanol at room temperature, and the mixture was stirred at50° C. for 8 hr. The reaction mixture was neutralized with a diluteaqueous sodium bicarbonate solution and was extracted with methylenechloride. The organic layer was washed with a 5% aqueous sodiumbicarbonate solution and a 20% aqueous sodium chloride solution in thatorder and was dried over anhydrous magnesium sulfate. The solvent wasremoved by evaporation to give a crude product of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.Toluene (5 ml) was added to the crude product, and the mixture washeated under reflux for 2.5 hr. The solvent was removed by evaporation,and the residue was purified by thin layer chromatography (developedwith 10% methanol/methylene chloride) to give 64.1 mg of allyl(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate.This product was analyzed by NMR. The results were in agreement with theresults of analysis in Example 26.

Example 42(3S,4R)-3-[(1R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)-methyl]azetidin-2-one

In the same manner as in Example 32, 0.54 g of(3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-one was prepared from 0.36 g of2-bromo-7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazole and 1.09 gof(3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-(4-dimethylaminobenzoyloxy-carbonyl)ethyl]-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)-methyl]-azetidin-2-one.

¹H-NMR (CDCl₃) δ: −0.10 (6H, m), 0.80 (9H, 2s), 0.96 (3H, m), 1.46 (3H,m), 2.64-2.89 (3H, m), 3.53 (3H, 3s), 3.51-3.93 (1H, m), 4.82-5.34 (2H,m), 6.71 (2H, d, J=8.5 Hz), 7.26 (1H, m), 7.48-7.91 (16H, m), 7.99 (1H,s), 8.20 (2H, d, J=8.5 Hz), 8.52 (1H, m), 8.75 (1H, m).

MS (FAB⁺) m/z 1012 (MH⁺)

Example 43(3S,4R)-3-[(1R)-1-Hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-one

In the same manner as in Example 36, 84 mg of(3S,4R)-3-[(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenyl-phosphoranylidene)methyl]azetidin-2-one wasprepared from 110 mg of(3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-one. This product was analyzed byNMR. The results were in agreement with the results of analysis inExample 29.

MS (FAB⁺) m/z 852 (MH⁺)

Example 44 (4-Nitrobenzyl)(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 30, 48 mg of (4-nitrobenzyl)(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylatewas prepared from 84 mg of(3S,4R)-3-[(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-one.This product was analyzed by NMR. The results were in agreement with theresults of analysis in Example 30.

MS (FAB⁺) m/z 574 (MH⁺)

Example 45(3S,4R)-1-[Allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one

(a)(3S,4R)-1-[(Allyloxycarbonyl)hydroxymethyl]-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

A solution of 45 mg of allyl glyoxylate monohydrate in 1.5 ml oftoluene, 266 mg of anhydrous sodium sulfate, and 1 ml of toluene wereadded to a suspension of 104 mg of(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-onein 0.5 ml of toluene at room temperature under an argon atmosphere, andthe mixture was then stirred at 70° C. for 3 days. The reaction mixturewas allowed to cool to room temperature and was diluted withtetrahydrofuran. The insolubles were then removed, and the solvent wasremoved by evaporation to give a crude product of(3S,4R)-1-[(allyloxycarbonyl)hydroxymethyl]-3-[(1R)-1-(tert-butyldimethylsilyloxy)-ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

(b)(3S,4R)-1-[(Allyloxycarbonyl)chloromethyl]-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one

A solution of the crude product of(3S,4R)-1-[(allyloxycarbonyl)hydroxymethyl]-3-[(1R)-1-(tert-butyldimethylsilyloxy)-ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-onein 1 ml of tetrahydrofuran was cooled to −50° C. under an argonatmosphere. A solution of 0.028 ml of pyridine in 1.5 ml oftetrahydrofuran and a solution of 0.025 ml of thionyl chloride in 1.5 mlof tetrahydrofuran were added thereto in that order. After thetemperature was brought to −20° C., the mixture was further stirred atthat temperature for one hr. The reaction mixture was diluted withtetrahydrofuran, and the insolubles were then removed. The solvent wasremoved by evaporation to give a crude product of(3S,4R)-1-[(allyloxycarbonyl)chloromethyl]-3-[(1R)-1-(tert-butyldimethylsilyloxy)-ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

(c)(3S,4R)-1-[Allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethylazetidin-2-one

Triphenylphosphine (92 mg) was added to a solution of the crude productof(3S,4R)-1-[(allyloxycarbonyl)chloromethyl]-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-onein 2 ml of dimethylformamide under an argon atmosphere at roomtemperature, and the mixture was stirred at that temperature for 20 hr.The reaction mixture was diluted with ethyl acetate, saturated brine wasadded to the diluted reaction mixture, and the mixture was neutralizedwith sodium hydrogencarbonate, followed by extraction with ethylacetate. The organic layer was washed with saturated brine and was thendried over anhydrous magnesium sulfate. The solvent was removed byevaporation to give a crude product of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.

(d) (3S,4R)-1-[Allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one

A 5 N aqueous hydrochloric acid solution (1 ml) was added to a solutionof (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)-methyl]-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-dimethoxy(pyridin-3-yl)methylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]-azetidin-2-onein 1 ml of methanol, and the mixture was stirred at 45° C. for 30 min.The reaction mixture was allowed to cool to room temperature, ethylacetate and 10% sodium chloride were added thereto, and the aqueouslayer was washed with ethyl acetate. The aqueous layer was neutralizedwith sodium hydrogencarbonate and was then extracted with ethyl acetate.The organic layer was washed with saturated sodium hydrogencarbonate andsaturated brine in that order and was then dried over anhydrousmagnesium sulfate. The solvent was removed by evaporation, and theresidue was purified by column chromatography on silica gel to give 30mg of(3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}azetidin-2-one.The results of analysis by NMR and MS were in agreement with the resultsof analysis in Example 36.

Example A-1 Allyl(1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylateiodide

2-Iodoacetamide (1.13 g) was added to a solution of 1.46 g of allyl(1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonyl-imidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate in 4.5 ml of methanol, and the mixture wasstirred at 40° C. for 22 hr. Methanol (8 ml) was added thereto fordilution. The diluted reaction mixture was added dropwise to 180 ml ofethyl acetate, and the resultant powder was collected by filtration togive 1.80 g of allyl(1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylateiodide.

¹H-NMR (DMSO-d₆) δ: 1.18 (3H, d, J=6.3 Hz), 1.24 (3H, d, J=7.1 Hz), 3.43(1H, dd, J=2.5, 5.5 Hz), 3.74-3.85 (1H, m), 3.98-4.35 (1H, m), 4.35 (1H,dd, J=2.7, 9.6 Hz), 4.70-4.90 (2H, m), 5.17 (1H, d, J=5.2 Hz), 5.23-5.39(1H, m), 5.42-5.50 (1H, m), 5.55 (2H, s), 5.90-6.03 (1H, m), 7.76 (1H,s), 8.07 (1H, s), 8.37 (1H, dd, J=6.3, 8.2 Hz), 8.58 (1H, s), 8.71 (1H,s), 9.15 (1H, d, J=6.3 Hz), 9.58 (1H, d, J=8.2 Hz), 9.76 (1H, s)

Example A-2(1S,5R,6S)-2-[7-(1-Carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate

A solution of 0.28 g of dimedone, 0.13 g of sodium bicarbonate, and 0.06ml of triethyl phosphite in 1 ml of water and 3 ml of tetrahydrofuranwas stirred at room temperature for 10 min. The atmosphere was thenreplaced by argon, 22.4 mg of palladium acetate was added thereto, andthe mixture was stirred for 10 min. Allyl(1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylateiodide (0.66 g) was added thereto, and the mixture was stirred at 40° C.for 2 hr. The reaction mixture was stirred in an ice-water bath for 30min, and the resultant precipitate was collected by filtration to give0.47 g of a crude product of(1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate.This crude product was dissolved in 2 ml of water, and the solution wasfiltered through a filter with a pore diameter of 0.45 μm, followed bywashing three times with 0.5 ml of water. The filtrate and the washliquids were combined, and stirring was carried out at 4° C. for 12 hr.The resultant precipitate was collected by filtration to give 0.35 g of(1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate.

¹H-NMR (DMSO-d₆) δ: 1.15-1.25 (6H, m), 3.15 (1H, dd, J=2.7, 6.9 Hz),3.43-3.53 (1H, m), 3.90-4.00 (1H, m), 4.10 (1H, d, J=2.5, 9.3 Hz), 5.07(1H, d, J=5.2 Hz), 5.07-5.20 (2H, m), 7.75 (1H, s), 8.28 (1H, s), 8.34(1H, s), 8.31-8.36 (2H, m), 9.15 (1H, d, J=6.3 Hz), 9.51 (1H, d, J=8.2Hz), 9.79 (1H, s)

Example A-3(1S,5R,6S)-2-[7-(1-Carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate

Sodium bicarbonate (6.72 g), 10.4 ml of N-methylaniline, and 4.8 ml oftriethyl phosphite were added in that order to 320 ml of a mixed liquidof 2-propanol:water=3:2. The atmosphere was replaced by argon, and themixture was stirred at room temperature for 15 min. Palladium acetate(0.90 g) was then added thereto, and the mixture was stirred for 10 min.A solution of 59.31 g of allyl(1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylateiodide in 400 ml of a mixed liquid of 2-propanol:water=3:2 was added tothe reaction mixture, and the mixture was stirred at 30° C. for one hr.2-Propanol (80 ml) was added to the reaction mixture, and the mixturewas stirred in an ice-water bath for one hr. The resultant precipitatewas then collected by filtration and was washed with 265 ml of a cooledmixed liquid of 2-propanol:water=2:1, 53 ml of 2-propanol, and 106 ml ofacetone in that order to give 7.168 g of(1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate.This product was analyzed by NMR. The results were in agreement with theresults of analysis in Example A-2.

¹H-NMR (DMSO-d₆) δ: 1.15-1.25 (6H, m), 3.15 (1H, dd, J=2.7, 6.9 Hz),3.43-3.53 (1H, m), 3.90-4.00 (1H, m), 4.10 (1H, dd, J=2.5, 9.3 Hz), 5.07(1H, d, J=5.2 Hz), 5.07-5.20 (2H, m), 7.75 (1H, s), 8.28 (1H, s), 8.34(1H, s), 8.31-8.36 (2H, m), 9.15 (1H, d, J=6.3 Hz), 9.51 (1H, d, J=8.2Hz), 9.79 (1H, s)

1. A compound represented by formula (1):

wherein R¹ represents a hydrogen atom or a protective group of hydroxyl,R² represents a hydrogen atom, a protective group of carboxyl, or ananion in a carboxylate anion, Z¹ and Z² together represent an oxygenatom or a protective group of carbonyl, or one of Z¹ and Z² represents ahydrogen atom and the other represents hydroxyl or protected hydroxyl, Yrepresents an oxygen atom or group P(R³)₃, wherein R³s, which may be thesame or different, represent C1-6 alkyl optionally substituted by ahalogen atom, or aryl optionally substituted by a halogen atom or C1-6alkyl in which the alkyl group may be substituted by a halogen atom. 2.The compound according to claim 1, wherein Y represents an oxygen atom.3. The compound according to claim 1, wherein Y represents group P(R³)₃.4. The compound according to claim 3, wherein R³ represents phenyl. 5.The compound according to claim 1, wherein R¹ is selected from the groupconsisting of a hydrogen atom, t-butyldimethylsilyl, trimethylsilyl, andtriethylsilyl.
 6. The compound according to claim 1, wherein R² isselected from the group consisting of a hydrogen atom, an anion incarboxylate anion, 4-nitrobenzyl, 4-methoxybenzyl, diphenylmethyl,allyl, and, t-butyldimethylsilyl.
 7. The compound according to claim 1,wherein Z¹ and Z² together represent a group selected from the groupconsisting of an oxygen atom, dimethoxy, diethoxy, anddimethylhydrazone, or one of Z¹ and Z² represents a hydrogen atom andthe other represents hydroxyl, or represents hydroxyl protected by agroup selected from the group consisting of t-butyldimethylsilyl,trimethylsilyl, and triethylsilyl.
 8. A process for producing a compoundrepresented by formula (1) according to claim 1 wherein Y representsgroup P(R³)₃, said process comprising the step of reacting a reactionmixture, prepared by treating a compound of formula (4′) with a Grignardreagent, with a compound of formula (5):

wherein Z¹¹ and Z¹² together represent an oxygen atom or a protectivegroup of carbonyl, or one of Z¹¹ and Z¹² represents a hydrogen atom andthe other represents protected hydroxyl, and X represents a halogenatom; and

wherein R¹¹ represents a protective group of hydroxyl, R² and R³ are asdefined in formula (1), and R⁴ represents optionally substituted C1-6alkyl, or aryl optionally substituted by a group selected from the groupconsisting of a halogen atom, optionally substituted C1-6 alkyl,optionally substituted C1-6 alkoxy, and —NR⁵R⁶, wherein R⁵ and R⁶, whichmay be the same or different, represent C1-6 alkyl, or R⁵ and R⁶together represent —(CH₂)_(n)— wherein n is an integer of 2 to
 6. 9. Theprocess according to claim 8, wherein Y in formula (1) represents groupP(C₆H₅)₃.
 10. The process according to claim 8, wherein said treatmentwith the Grignard reagent is carried out using an alkylmagnesium bromideas the Grignard reagent in a solvent selected from the group consistingof methylene chloride, ether, tetrahydrofuran, dioxane, benzene, andtoluene.
 11. The process according to claim 8, which further comprisespreparing the compound of formula (4′) by steps (c) and (d): (c)formylating a compound of formula (14) with a Vilsmeyer complex to givea compound of formula (18):

wherein X represents a halogen atom, and

wherein X represents a halogen atom, and (d) reacting the compound offormula (18) with a 3-metallopyridine of formula (19) to give a compoundof formula (4′) in which one of Z¹¹ and Z¹² represents a hydrogen atomand the other represents hydroxyl, and either protecting hydroxyl inthis compound, or oxidizing hydroxyl in this compound and protectingcarbonyl in the resultant compound, to give the compound of formula(4′):

wherein M represents lithium, MgBr, or MgI.
 12. The process according toclaim 11, which further comprises preparing the compound of formula (14)by steps (a) and (b): (a) reacting a compound of formula (15) with ahalogenating agent to give a compound of formula (16) and formylatingthe amino group optionally after removing the protective group, to givea compound of formula (17):

wherein R⁸ represents a hydrogen atom, or a protective group of aminoand X represents a halogen atom, and (b) reacting the compound offormula (17) with a dehydrating agent for cyclization to give a compoundof formula (14).
 13. A process for producing a compound represented byformula (1) according to claim 1 wherein Y represents an oxygen atom,said process comprising the step of reacting a compound of formula (8)with a compound of formula (9) in the presence of a base:

wherein R⁷ represents a hydrogen atom, or a protective group of amino,R¹, R², Z¹ and Z² are as defined in formula (1), and L² represents aleaving group.
 14. The process according to claim 13, which furthercomprises preparing the compound of formula (8) by step (f): (f)reacting a compound, prepared by treating a compound of formula (6′)with an alkali metal base, or a base and a monovalent to tetravalentmetal compound, with a compound of formula (7), and optionally removinga protective group and/or introducing a protective group and/orconducting oxidization to give a compound of formula (8):

wherein Z¹¹ and Z¹² together represent an oxygen atom, or a protectivegroup of carbonyl, or one of Z¹¹ and Z¹² represents a hydrogen atom andthe other represents protected hydroxyl; and

wherein R¹¹ represents a protective group of hydroxyl, R⁷ represents ahydrogen atom or a protective group of amino, and L¹ represents aleaving group.
 15. The process according to claim 14, which furthercomprises preparing a compound of formula (6′) by steps (c), (d) and(e): (c) formylating a compound of formula (14) with a Vilsmeyer complexto give a compound of formula (18):

wherein X represents a halogen atom, (d) reacting the compound offormula (18) with a 3-metallopyridine of formula (19) to give a compoundof formula (4′) wherein one of Z¹¹ and Z¹² represents a hydrogen atomand the other represents hydroxyl, and either protecting hydroxyl inthis compound, or oxidizing hydroxyl in this compound and protectingcarbonyl in the resultant compound, to give a compound of formula (4′):

wherein M represents lithium, MgBr, or MgI, and (e) reacting a compound,prepared by treating the compound of formula (4′) with a Grignardreagent, with a propionic acid derivative to give a compound of formula(6′).
 16. The process according to claim 15, wherein said Grignardreagent is selected from the group consisting of alkylmagnesiumchlorides, alkylmagnesium bromides, alkylmagnesium iodides, andarylmagnesium bromides, and said propionic acid derivative is selectedfrom the group consisting of N-methyl-N-methoxypropionamide, propionicanhydride, propionyl chloride, and propionic acid(pyridin-2-ylthio)ester.
 17. The process according to claim 15, whichfurther comprises preparing a compound of formula (14) by steps (a) and(b): (a) reacting a compound of formula (15) with a halogenating agentto give a compound of formula (16) which, optionally after the removalof a protective group, undergoes formylation of amino to give a compoundof formula (17):

wherein R⁸ represents a hydrogen atom, or a protective group of amino,and X represents a halogen atom, and (b) reacting the compound offormula (17) with a dehydrating agent for cyclization to give a compoundof formula (14).
 18. A process for producing a compound represented byformula (1) according to claim 1 wherein Y represents group P(R³)₃, saidprocess comprising the steps of halogening hydroxyl in a compound offormula (11), prepared by reacting a compound of formula (8) with acompound of formula (10) or its reactive equivalent, with a halogenatingagent, and reacting the resultant compound with a compound of formula(13):

wherein R¹¹ represents a protective group of hydroxyl, R¹, R², and R³are as defined in formula (1), R⁷ represents a hydrogen atom, Z¹ and Z²together represent an oxygen atom, or a protective group of carbonyl,or, one of Z¹ and Z² represents a hydrogen atom and the other representshydroxyl or protected hydroxyl, Z¹¹ and Z¹² together represent an oxygenatom, or a protective group of carbonyl, or one of Z¹¹ and Z¹²represents a hydrogen atom and the other represents protected hydroxyl.19. The process according to claim 18, wherein Y in formula (1)represents group P(C₆H₅)₃.
 20. The process according to claim 18, whichfurther comprises preparing a compound of formula (8) by step (f): (f)reacting a compound, prepared by treating a compound of formula (6′)with an alkali metal base, or a base and a monovalent to tetravalentmetal compound, with a compound of formula (7), and optionally removinga protective group and/or introducing a protective group and/orconducting oxidization to give a compound of formula (8):

wherein Z¹¹ and Z¹² together represent an oxygen atom, or a protectivegroup of carbonyl, or one of Z¹¹ and Z¹² represents a hydrogen atom andthe other represents protected hydroxyl;

wherein R¹¹ represents a protective group of hydroxyl, R⁷ represents ahydrogen atom, or a protective group of amino, and L¹ represents aleaving group.
 21. A process for producing a compound represented byformula (2), said process comprising the steps of treating a compound offormula (1) according to claim 1 under conditions, which can form acarbapenem ring, to form a carbapenem ring through a ring-closingreaction and optionally conducting the removal of a protective groupand/or oxidation:

wherein R¹ represents a hydrogen atom, or represents a protective groupof hydroxyl, R represents a hydrogen atom, a protective group ofcarboxyl, or an anion in a carboxylate anion, Z¹ and Z² togetherrepresent an oxygen atom, or a protective group of carbonyl, or one ofZ¹ and Z² represents a hydrogen atom and the other represents hydroxylor protected hydroxyl.
 22. The process according to claim 21, wherein Yin formula (1) represents an oxygen atom.
 23. The process according toclaim 22, wherein the treatment for forming the carbapenem ring iscarried out by reacting the compound of formula (1) with a compound offormula (21):P(R⁹)₃  (21) wherein R⁹s, which may be the same or different, representC1-6 alkyl or C1-6 alkoxy.
 24. The process according to claim 23,wherein the compound of formula (21) is diethyl methylphosphonite. 25.The process according to claim 21, wherein Y in formula (1) is groupP(C₆H₅)₃.
 26. The process according to claim 25, wherein the treatmentfor forming the carbapenem ring is carried out by eliminating O═P(R³)₃from the compound of formula (1).
 27. A process for producing a compoundrepresented by formula (A), comprising the step of preparing thecompound of formula (2) from the compound of formula (1) by a processaccording to claim 21:


28. The process according to claim 27, which further comprises the stepof reacting the compound of formula (2) with a compound of formula (Iv)to give a compound of formula (3):

wherein L³ represents a leaving group, R¹ represents a hydrogen atom, orrepresents a protective group of hydroxyl, and R represents a hydrogenatom, a protective group of carboxyl, or an anion in a carboxylateanion.
 29. The process according to claim 28, which further comprisesthe step of removing the protective group in the compound of formula (3)by a deprotection reaction to give the compound of formula (A).
 30. Theprocess according to claim 27 further comprises the step of preparingthe compound of formula (1) by reacting a reaction mixture, prepared bytreating a compound of formula (4′) with a Grignard reagent, with acompound of formula (5),

wherein in formula (4′) Z¹¹ and Z¹² together represent an oxygen atom ora protective group of carbonyl, or one of Z¹¹ and Z¹² represents ahydrogen atom and the other represents protected hydroxyl, and Xrepresents a halogen atom; and

wherein in formula (5) R¹¹ represents a protective group of hydroxyl. R²and R³ are as defined in formula (1), and R⁴ represents optionallysubstituted C1-6 alkyl, or aryl optionally substituted by a groupselected from the group consisting of a halogen atom, optionallysubstituted C1-6 alkyl, optionally substituted C1-6 alkoxy, and —NR⁵R⁶,wherein R⁵ and R⁶, which may be the same or different, represent C1-6alkyl, or R⁵ and R⁶ together represent —(CH₂)_(n)—, wherein n is aninteger of 2 to
 6. 31. A process for producing a compound represented byformula (14), comprising steps (a) and (b):

wherein X represents a halogen atom, (a) reacting a compound of formula(15) with a halogenating agent to give a compound of formula (16) which,optionally after the removal of a protective group, undergoesformylation of amino to give a compound of formula (17):

wherein R⁸ represents a hydrogen atom, or a protective group of amino,and X represents a halogen atom, and (b) reacting the compound offormula (17) with a dehydrating agent for cyclization to give a compoundof formula (14).
 32. The process according to claim 31, wherein Xrepresents a bromine atom.
 33. A compound represented by formula (4):

wherein Z¹ and Z² together represent an oxygen atom, or a protectivegroup of carbonyl, or one of Z¹ and Z² represents a hydrogen atom andthe other represents hydroxyl or protected hydroxyl, and X represents ahalogen atom.
 34. A compound represented by formula (6):

wherein Z¹ and Z² together represent an oxygen atom, or a protectivegroup of carbonyl, or one of Z¹ and Z² represents a hydrogen atom andthe other represents hydroxyl or protected hydroxyl.
 35. A compoundrepresented by formula (8):

wherein R¹ represents a hydrogen atom, or represents a protective groupof hydroxyl, Z¹ and Z² together represent an oxygen atom, or aprotective group of carbonyl, or one of Z¹ and Z² represents a hydrogenatom and the other represents hydroxyl or protected hydroxyl, and R⁷represents a hydrogen atom, or a protective group of amino.
 36. Acompound represented by formula (14a):


37. A method of producing an antimicrobial agent, wherein the compoundaccording to claim 1 is used as a synthetic intermediate for theproduction of the antimicrobial agent.